After members of his Cabinet spent the weekend talking up life outside the EU, David Cameron now has to highlight the benefits of a possible trade deal between the United States and Europe.
The Prime Minister will be talking up the plan as he holds talks with Barack Obama in the White House on Monday.
He is to argue that an agreement could be worth up to £10 billion a year to the economy.
However, he could also need to reassure the president about the UK's future within the grouping, amid ongoing Tory skirmishing on the issue.
Cabinet ministers Michael Gove and Philip Hammond yesterday became the latest senior figures to indicate they would currently vote to leave the EU - a prospect which alarms the US administration.
Mr Cameron hopes to focus on trade liberalisation, development and Syria during his three-day visit to America, but is unlikely to be able to escape the EU row raging at home.
The two leaders will be joined in the Oval Office by US secretary of state John Kerry, Mr Cameron's national security adviser Kim Darroch, and opposite number Tom Donilon.
The Prime Minister will urge a peace conference on Syria by the end of the month. He believes efforts to end the 27 month conflict have gained some momentum after his trip to Sochi for talks with President Vladimir Putin last week,
and Mr Kerry's visit to Moscow.
Russian support for Bashar Assad's regime has been one of the main obstacles to easing the situation, but the West has appeared split on whether to respond by arming rebels.
Mr Cameron will raise the prospect of using next month's G8 summit in Northern Ireland to launch negotiations for an EU-US trade deal.
Writing in the Wall Street Journal, Mr Cameron said: "When times are tough, some want to put the barriers up, to look inwards, and to protect themselves from the world.
"But Britain and America stand for a better way. We have a precious opportunity to transform the global economy - not by less openness and less free trade, but by more. And we must do everything possible to seize it.
"Trade is not a zero sum game where one nation's success is another's failure. Trade makes the cake bigger so everyone can benefit. Take the free trade area between Europe and the US on which we hope to launch negotiations when President Obama is in Northern Ireland for the G8 next month.
"This deal could add as much as £10 billion to the British economy and £63 billion to US GDP.
"But the rest of the world would benefit too, with gains that could generate 100 billion euros worldwide."
Mr Cameron is calling for US co-operation to get tough G8 action on tax evasion and aggressive tax avoidance.
Beforehand, Mr Cameron and new director of MI5 Andrew Parker will tour the state-of-the-art FBI headquarters in Washington.
The premier has asked for a briefing from FBI chief Robert Mueller to see if there are any lessons the UK can learn from the Boston marathon attack.
Mr Cameron will go to that city later in his trip, before heading on to New York for a United Nations high-level panel meeting.
Speaking to reporters on the plane to the US, Mr Cameron struck a positive note on prospects for movement on Syria.
He played down apparent differences of approach with Washington, saying there was "very strong unity of purpose between Britain and America that we should be working very closely with the rebels".
"But I think there is also something bigger happening here which is a realisation that it would be far better if what we could do is bring about a political transition through a greater engagement and agreement between America, Russia, Britain, France, other powers," he said.
"While it is no secret that Britain and Russia have taken a different approach to Syria I was very struck in my conversations with President Putin that there is a recognition that it would be in all our interests to secure a safe and
secure Syria with a democratic and pluralist future, and end the regional instability.
"We have got a long way to go, but they were good talks."