Whichever side lost would just have to pick themselves up and "get on with the things that really matter", he said as a new poll suggested public opinion was hardening against change.
With less than two weeks until the May 5 poll, he waded into the row over campaign funding, backing Chancellor George Osborne against Lib Dem claims he was trying to "scare" voters.
But he said he hoped there would be a "reasonable argument on both sides" in the closing days of the campaign that would help to "fire up" a relatively uninterested public.
Securing a referendum on whether to abandon the first-past-the-post system for electing MPs in favour of the Alternative Vote (AV) was the key concession wrung by the Lib Dems as part of the coalition deal.
With imminent local elections putting an increasing strain on relations between the two parties, a public rejection of AV will heap still more pressure on Lib Dem leader Nick Clegg to pull out.
Speaking on the Murnaghan show on Sky News, Mr Cameron said: "I profoundly believe a 'no' vote is the right answer.
"We have got a system that is effective, that is simple, that is fair, that works, that is used by half the world and we shouldn't swap it for a system that is unfair and used by just a handful of countries and that is much more complicated. It should be a reasonable argument on both sides."
Asked if victory could destroy the power-sharing deal, he said: "Whatever the result on May 5, this is a five-year Government, Nick and I are absolutely committed to taking the Government and its programme forward."
"Whoever is on the losing side as it were will just have to pick themselves up and say: well, it was a fair argument, a fair fight, a fair referendum, the country has decided and now we have got to get on with all the things that really matter so much."
The Lib Dems had "made a real difference" to the direction of Government, he said.
Mr Cameron said Mr Osborne had simply been stating "fact" when he suggested that the commercial arm of the 'yes' campaign's biggest financial backer stood to profit from a switch to AV.
Electoral Reform Services Limited - which gives some of its profits from helping run ballots to 'yes' campaign backer the Electoral Reform Society - firmly denies any such conflict of interest.
In a vituperative attack on the Chancellor, Lord Ashdown said his strategy "stinks of the same odour which has surrounded our politics recently" and accused him of hiding the facts from voters.
But Mr Cameron said: "The point that George Osborne made that the Electoral Reform Society is a big funder of the 'yes' campaign but it has an organisation that could make money out of it - that's a fact and I think there is nothing wrong about bringing that fact out."
A ComRes survey for the Independent on Sunday and Sunday Mirror gave the "no" camp a six-point lead, an exact reversal of the position as recently as January as more undecided voters make up their minds.
The campaign is set to shift up another gear this week as senior politicians from both camps take to the stage for a final push ahead of the poll.
Much of the debate so far has been dominated by spats over funding, poll data and celebrity backers which Mr Cameron conceded had failed to engage voters.
"The most important thing we've got to do is try and explain to the public, who aren't absolutely fired up about this issue, why it matters," he said.
"What we've got to do in the closing days of this campaign is really focus on what the change would mean," he said.
Mr Cameron said both his party and the Lib Dems could point to "real things" that they had secured in Government.
"I don't know what that result is going to be but whatever it is, the Coalition Government I believe, will go on being a strong and effective government," he said,
"The most important thing we've got to do is get the economy moving and pay down the debts."
Writing in the Observer, Lord Ashdown launched a fierce attack on the "no" camp - which politically includes almost all Tory MPs as well as at least 100 from Labour despite Opposition leader Ed Miliband's support for AV.
"Their strategy is clear: throw as much mud as you can, don't let the issue be discussed openly and frighten the public over the next three weeks into voting to preserve the power the present First Past the Post system gives them.
"This strategy stinks of the same odour which has surrounded our politics recently. For the Chancellor of the Exchequer - the Chancellor of the Exchequer - to claim that there is something 'dodgy' about the Electoral Reform Society donating cash to a campaign in favour of electoral reform is bizarre.
"George Osborne makes the case for change for us. He graphically shows why we need to change our politics. Why we need to clean it up. Why the voting public deserve something better."
He said he respected opposing views, but said he was "perplexed and deeply disturbed...that those running the 'No' campaign haven't once put forward a positive case for the current system and, instead have spent their time lying about AV".
The poll - weighted to reflect those certain to vote - found 37% backed AV with 43% against - compared with a 36% to 30% split the other way in January.
Responding to the poll, Matthew Elliott, Campaign Director of NO to AV, said: "The polls show that as people are learning more about the complex, unfair and expensive Alternative Vote system, they understand why it is completely the wrong sort of change.
"There is much work still to be done to make sure the UK isn't saddled with a £250 million mess, but it is encouraging that the British people know a very bad idea when they see it."
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