Ahead of an eagerly-anticipated speech on the EU by David Cameron, in which he was expected to offer a referendum after 2015, the Deputy Prime Minister questioned why there should be "a great national debate about nothing very much in particular".
Speaking to journalists in Westminster, he said he was "certainly not frightened" of a referendum, and had supported legislation requiring one if new powers were passed to Brussels.
But he said: "We don't know whether there is going to be a new treaty, lots of people in the eurozone say they want to avoid a treaty like the plague. And even if they have a new treaty we don't know what it will say, we don't know what it will ask of Britain, if anything.
"It's not whether you think a referendum's a good idea or not it's why would you provoke a great national debate about nothing very much in particular in response to a document that hasn't materialised yet and might never materialise."
His comments, during a House of Commons press gallery lunch, came after the US assistant secretary for European affairs Philip Gordon expressed concern about the prospect of the UK moving to the sidelines of the European Union.
The unusually direct intervention by the Obama administration provoked a furious backlash from Tory eurosceptics who want to see the UK loosen its ties with the EU. But Mr Clegg, in a phone-in on LBC radio, said that Mr Gordon's comments were "entirely unsurprising".
Asked later whether he still backed an in/out referendum - as promised in the Liberal Democrats' 2010 manifesto - Mr Clegg said: "I think almost regardless of whatever question you put in any eventual referendum, the underlying question is the same - does Britain want to lead in Europe and continue to lead...
"Do we lead or do we kind of hang back in a sort of subsidiary status? And I just think not only ourselves but the Americans and others quite understandably say you are a big nation, you've got big horizons, you've got big ambitions, you've got a big history, act big, don't act small."