To date, the OU has won the series only once - back in 1985 - though it came tantalisingly close in 1997 when it reached the final, scoring 415 points in one round.
Can a team of scattered part-timers with distracting jobs and family commitments hold their own against the bright young (and not so young) minds of full-time students? Who are the brains upholding the OU's honour this year?
Your starter for ten...
John Burke, 39, part-time postman from Faversham, the team captain. Main area of study Arts, has just achieved a Diploma in European Humanities on the way to a BA. Hobbies: Architecture, history, music, European travel, pubs, football.
At first glance John looks the very opposite of a stereotypical intellectual. He's a big man with a powerful personality, who enjoys his beer, a game of soccer, going down the pub.
But even a quick chat uncovers a fund of general knowledge and breadth of interests above the norm - ranging from the history of London churches to Carry On films.
Born in London and passionately interested in its history and architecture (he's writing a book on City of London churches) he spent many of his formative years in a pub - his father ran St George's Tavern in Camberwell when John was in his teens. He says it was "a good education in real life".
His current occupations, apart from paid employment and his book, include acting as a guide to London landmarks, and building detailed architectural models for a museum.
Says John: "As captain, you need a fairly wide knowledge - to know something about most things. If two people on your team are giving you different answers, you need to have a feel for which may be right. You also need authority."
As a team, OU contestants have the disadvantage of being geographically scattered - they can't come together in the student union bar to get to know each other.
The first time the whole OU team met face-to-face was before their first competition in the preliminary selection rounds that take place to decide which will be the 24 teams who actually appear on University Challenge.
As captain, John did his best to find out their individual strengths and weaknesses in advance: "I asked everyone to let me have their CVs, and tell me what they are best at. I think as a team we jelled well."
His approach to University Challenge is not dissimilar to the way he approaches a game of football - he plays to win, but doesn't let defeat upset him unduly.
The word 'nervous' simply doesn't figure much in John's vocabulary: "You just do your best, and you can't do any more."
David Good, from High Wycombe, computer software developer, main area of study computer sciences.
At 32, the baby of the team, David is also the quiet one - a contrast to his three team members who are all ebullient and talkative personalities.
He went to conventional university but dropped out after a year - " I had no motivation". He worked as " paper pusher" for the Foreign Office before changing career to become a computer software developer.
He's been an OU student since 1993, having achieved his BSc last year and hoping to make it Honours this year.
Five years ago he joined a local quiz league but his involvement dropped off after the birth of his son, now nearly two.
He applied to go on University Challenge in the year the OU made it to the final but (to his great disappointment) wasn't selected. David doesn't admit to any speciality but says he's an " all rounder".
"Comparing us to the 1997 team, I'm not sure any one person on this team is as good as Martin Heighway, but everyone is pretty good. We are not carrying any passengers. We have John who is a genuine expert on architecture; Lance on Classics and Sue on astronomy."
Is he looking forward to the semi-final. "I'm nervous," he admits, "particularly as the teams have been told that for the semi finals the questions will be made more difficult." Nevertheless, he says University Challenge is "one of the best experiences I have had over the last ten years".
Lance Hayward of London, retired lawyer. Hobbies: Music, travel, archaeology, public speaking, skiing, horses, indoor games. Main area of study: Classical Greek.
Three times Brain of Mensa, twice a finalist on Brain Of Britain, appearances on Mastermind, 15 to 1 and many others? Is Lance a quiz addict?
He gives a lawyer's reply: " If, having done University Challenge, I look around and see nothing else worth doing - and I feel no withdrawal symptoms - does that make me an addict?"
Although retired he does a little consultancy work in his specialist area, educational law. Currently one his main preoccupations is putting on a cabaret show in Highgate to raise money for local churches - he's producing, writing and acting in it.
As a quiz contestant Lance is not known for his meekness: "A lawyer's brain puts you in a position to challenge half the answers, because of the way they are drafted."
Has he got any tips on winning at quiz shows?
"The subconscious knows things your conscious mind doesn't. You may hear a question and think you ought to know the answer, so you buzz. After you've buzzed you're thinking, What the hell is the answer? You open your mouth to say something - anything - and your subconscious takes over and the answer comes out."
Useful subjects to be genned up on prior to embarking on a quiz, he suggests, include: American state capitals, atomic elements, Gilbert and Sullivan operettas, kings and queens of England (foreign monarchs only if there's some colourful history attached to them), Shakespeare, the Bible (whatever your personal religious beliefs), heraldry and Greek mythology.
At 62, Lance is the oldest team member. Is that a disadvantage? Not particularly, he says.
"The physical reflexes are slower - the finger on the buzzer. But I think the mental processes are just as acute."
And, no, he's not nervous, either. "I'm probably the most laid back person in the studio apart from Jeremy Paxman. It's down to age and habit and familiarity - having done thirteen or fourteen quiz programmes - it just becomes routine. You don't think of the 20 million people looking in - you just see this rather small studio audience, some of whom you know."
Sue Mitchell, 51, from Grimsby, supply teacher, main area of study Humanities. Hobbies: History, music, literature, astronomy, and the Grimsby Distance Quiz League.
Sue got ten O-levels at school but lost interest in going to university after she wasn't allowed to study the A-levels she wanted. She trained as a teacher, but her main career so far has been bringing up her two children, now aged 22 and 20. She opted for OU study " to fill in the gap between raising children and senility". She enjoys writing fiction in the fantasy 'wizards and warriors' genre and hopes to become a published writer.
As a woman contestant, she's in a minority. Women make up a little over half the undergraduate population, but conspicuously fewer than half of the University Challenge contestants. This comes as no surprise to Sue:
"University Challenge is not unusual. I've noticed that on quiz programmes in general, men predominate. In our quiz league only about 10% are women." She thinks it may be "because women have better things to do"...
"I also think women are more self-conscious and sensitive about looking like idiots - and on University Challenge there is plenty of scope for looking like an idiot. You feel very exposed.
"Perhaps also women tend to be more concerned about their appearance and how they are coming over. If you do that you'll be less focused on the questions."
Dress-wise, Sue's main concern is which of her selection of butterfly-embroidered T-shirts to wear. Butterflies are her lucky talisman.
"I wore my royal-blue one for the first round, cerise for the second and for the quarter final. We had the largest win in the first round, so for the semi I'm going back to royal-blue."
Like the other team members, she admires Jeremy Paxman's professionalism:
"He rattles off those difficult chemical names... People who watch him may think he is a bit sarcastic at times, but it's not directed at anybody. If you say something stupid he might make some comment about it, but he's not saying you are stupid, just that the thing you said wasn't really terribly bright."
A few facts
By the time teams appear on your screen in the first round of University Challenge they've already been through a tough selection process. Around 250 universities and colleges apply for entry, and are subjected to a round of interviews to reduce their number down to just 24 teams.
The OU has had a team in all of the last five series, and is the only university to do so. Between 1994 and 1998 they held the record for the highest score - 415 - and the highest winning margin. But no overall victory.
You can see the OU and other teams in the semi-finals of University Challenge on BBC2 on Wednesdays during April.