Uncapped Gloucester centre Billy Twelvetrees will make his England debut in Saturday's Calcutta Cup game against Scotland after being selected in place of the injured Manu Tuilagi.
Twelvetrees will become the 18th new player capped by head coach Stuart Lancaster in 13 Tests when he lines up alongside Brad Barritt in a rejigged England midfield for the RBS 6 Nations opener.
Barritt will revert to the outside centre role he filled on his own Test debut in last year's Calcutta Cup win at Murrayfield, with Twelvetrees operating on his inside.
Joe Marler has returned at loosehead prop in place of Alex Corbisiero, who has been ruled out of the Six Nations with a knee problem.
Other than the two injury-enforced changes, Lancaster has retained the starting line-up that laid the foundations for England's record 38-21 victory over New Zealand two months ago.
That means Tom Youngs keeps the hooker's jersey ahead of the more experienced Dylan Hartley, who missed the autumn series through injury.
Ben Youngs has held off the challenge from Danny Care to keep hold of the scrum-half position and Alex Goode returned from a shoulder injury in time to retain the full-back berth.
"We are happy to stick with the team that did so well against New Zealand, especially in light of the fact that they have all been in good form for their clubs since then," Lancaster said.
"There were some very tight calls, with some experienced players coming back into contention, and I am sure the bench will have a significant impact on the game."
Leicester fly-half Toby Flood, the most experienced player in the 23-man squad with 53 caps, comes onto the bench along with Saracens wing David Strettle.
Tuilagi is expected to be available for England's second Six Nations appointment, against Ireland in Dublin a week on Sunday.
Twelvetrees is not a like-for-like replacement but he has a more rounded game than Tuilagi, offering a kicking game and a presence as a second playmaker outside Farrell.
The 24-year-old is also a powerful ball-carrier and defender, prompting Gloucester's director of rugby Nigel Davies to enthuse that he is the complete package for an inside centre.
Lancaster said: "This is a great opportunity for Billy.
"I coached him in the Churchill Cup. It was a winning side, he played number 12 and I could see then he had lots of potential and physicality.
"Moving to Gloucester has been a big help. His confidence has shone through.
"I have every confidence in him going into the game.
"Sometimes opportunities present themselves in different ways. We know Manu is going to be fit for next week and we hope Billy puts a marker down this week and gives us another headache."
Lancaster's toughest decision was at scrum-half but it was one of a number of tight calls.
"Nine is the position I spend the most time thinking about," Lancaster said.
"Ben Youngs gets the start this time and Dandy (Care) will come off the bench but both will get their turn during the Six Nations.
"It was a tight call there and at hooker. Tom played very well in the autumn. Dylan comes back into the equation but I need to reward the player who is in the shirt.
"It's not a given but Tom has been outstanding since the New Zealand game for Leicester both in the Premiership and in Europe."
Marler was preferred to Mako Vunipola at loosehead and he returns to the front row, having missed the last two matches through injury.
"He was outstanding for us on the summer tour of South Africa," Lancaster said.
"He went up against the most formidable pack in world rugby and more than held his own. His form for Harlequins has been excellent and that is a prerequisite to playing for England."
Lancaster dismissed accusations of arrogance that were levelled at the England team by the former Scotland coach Jim Telfer.
"It might have been the case in the past but it is no resemblance to my team," said Lancaster, who set about changing the culture of the England camp when he first took charge a year ago.
"I am delighted with the progress we have made but I am disappointed not to have had that consistent run of wins. We beat New Zealand but we lost two other games in the autumn.
"We are striving for that consistency and we have some way to go to achieve that."
England return to Twickenham for the first time since their record victory over the All Blacks.
"We always had self-belief, what that win did was confirm to those outside the team that we have a group of players who will fight for the shirt."
England team to play Scotland in the RBS 6 Nations at Twickenham on Saturday, February 2 (kick-off 4pm)
A Goode (Saracens); C Ashton (Saracens), B Barritt (Saracens), B Twelvetrees (Gloucester), M Brown (Harlequins); O Farrell (Saracens), B Youngs (Leicester), J Marler (Harlequins), T Youngs (Leicester), D Cole (Leicester), J Launchbury (Wasps), G Parling (Leicester), T Wood (Northampton), C Robshaw (Harlequins, capt), B Morgan (Gloucester).
Replacements: D Hartley (Northampton), D Wilson (Bath), M Vunipola (Saracens), C Lawes (Northampton), J Haskell (Wasps), D Care (Harlequins), T Flood (Leicester), D Strettle (Saracens).