President Obama has said the United Kingdom would be at the "back of the queue" for any free trade deal with the United States if it decided to leave the European Union.
In a striking and lengthy intervention in the referendum debate, the president said while a deal would be possible it was "not going to happen any time soon".
The warning is a damaging blow to the pro-Brexit campaign - which has said the UK would be able to negotiate its own agreement with Washington.
Speaking at a press conference in London alongside David Cameron, Obama said: "This is a decision for the people of the UK to make. I am not coming here to fix any votes. I am not casting a vote myself. I am offering my opinion.
"In democracies everybody should want more information, not less. And you shouldn’t be afraid to hear an argument being made. That’s not a threat, that should enhance the debate."
Obama said predictions that the UK would easily be able to sign a trade deal with the US were misplaced.
"It’s fair to say, maybe some point down the line, there might be a UK-US trade agreement. But it's not going to happen any time soon. Our focus is negotiating with a big bloc, the EU, to get at trade agreement done. And the UK is going to be the back of the queue."
Those campaigning for the UK to leave the EU, including Boris Johnson, have said Obama should not intervene in an internal-British debate. However Cameron said it "makes sense to what our friends think, to listen to their opinion and their views".
Cameron insisted that the special relationship between the UK and US was not "constrained" by Britain's EU membership.
EU membership gave Britain "a powerful tool" to stand up for the values it shares with the US, said Cameron, adding: "Now, I think, is a time to stay true to those values, and to stick together with our friends and allies in Europe and around the world."
Obama added: "The UK is at its best when it's helping to lead a strong European Union. It leverages UK power to be part of the EU. I don't think the EU moderates British influence in the world, it magnifies it.
"America wants Britain's influence to grow, including within Europe.
"As part of our special relationship, part of being friends is to be honest and to let you know what I think, and speaking honestly, the outcome of that decision is a matter of deep interest to the US, because it affects our prosperity as well."
Ukip leader Nigel Farage responded immediately. "President Obama won't be in office by the time we're out of the EU post-referendum. Trade deal of course in both countries interests," he said.
Earlier today, Boris was accused of "racism" for calling Obama the "part-Kenyan president".
And Farage stoked further fury by claiming on the BBC’s The World At One programme that Obama "bears a bit of a grudge against this country" because of colonialism.