The Obama administration has made no bones about it - it wants a strong Britain within a strong Europe.
The President's press secretary, Jay Carney, has said that he welcomed the Prime Minister's call for Britain to remain in the European Union, adding that the US believed the UK was stronger for being in the EU, and the EU was stronger for having the UK as a member.
In the modern version of the special relationship, what Carney called the essential relationship, Britain is valued as an ally precisely because it is one of the leaders of the biggest economy in the world.
Some in Washington think Mr Cameron's speech threatens that role and introduce more unnecessary uncertainty to an already uncertain world.
Until recently, the promise of a referendum from Mr Cameron was seen in Washington as just another phase in the rocky relationship between the UK and continental Europeans.
But now alarm bells are ringing. The White House doesn't care about the EU's internal organisation, and Europe is hardly its biggest concern anyway, but Mr Cameron's promise is definitely an unwanted irritation.
Assistant Secretary of State for European affairs Phil Gordon has been unusually blunt. He is publicly saying that referendums could turn countries inwards.
"We have a growing relationship with the EU as an institution, which has an increasing voice in the world, and we want to see a strong British voice in that EU. That is in America's interests. We welcome an outward-looking EU with Britain in it," he said.
President Obama repeated this view in a phone call to Mr Cameron.
The Americans are worried for several reasons.
They fear the debate that will rage for the next few years will undermine Britain's voice in the EU and diminish its power.
Indeed, insiders say that has already happened - they find other EU members aren't taking Britain seriously.
While US officials would agree with Mr Cameron's push for a more competitive, less rule-bound Europe, they fear he will now be less able to achieve it.
There is internal politics too. There is an argument inside the administration over whether or not to seek a free-trade agreement with the EU.
Those who want to go ahead may fear their position has been undermined.
They may feel that Mr Cameron has given ammunition to those who argue it is not worth the bother. Some suggest it would be an irony if such a deal was negotiated - and Britain found itself outside the new free-trade area.
Although the prime minister clearly intends to sell a deal that keeps Britain inside the EU there are fears that he will fail.
The Obama administration values the European Union as an ally that largely shares its vision, and acts with it in the Middle East, over Iran and North Africa.
Officials will fret over the next few years that Britain really could leave and that would badly weaken the EU.
At the risk of hurting British egos, they simply don't see Britain - especially with a declining defence budget - as anything more than a medium-sized power in its own right.
As one insider put it to me: "At the moment Britain is a leader in the biggest economy in the world - what's the strategy for being out? Just trail around behind us?"