The UK is "valuable" to the US partly because it is a member of the EU, the deputy prime minister has said.
It comes after the Obama administration expressed concern about the impact of a UK referendum on its future in the EU.
Mr Clegg said if the UK wanted to lead in the world you had to be "strong in your neck of the woods".
No 10 said David Cameron wanted changes to EU relations, adding it was "hardly news" the two men took a different approach to the future of Europe.
Mr Clegg, who was speaking on the first of his weekly radio phone-ins on LBC, said it was up to the UK to decide how it handles its relationship with Europe, but the Americans were entitled to express their views.
He said: "Americans have been saying since the 1950s that Britain and the special relationship between Britain and America is one that is partly based on the fact that we're valuable to our American friends, and important to people in Beijing and Tokyo, because we stand tall in our own neighbourhood.
"If you want to lead around the world - and this a globalised environment we're working in - the first thing you've got to do is be strong in your neck of the woods and I think that's the point they're making."
The EU and the single market were crucial for British jobs and helped the UK tackle cross border crime, he added.