BP Plc's role in the US Gulf Coast oil spill and speculation about any influence the British oil giant may have had over the release of the Lockerbie bomber from a Scottish prison last year has complicated relations in the run-up to this week's talks.
Cameron's office has tried to play down the concern, saying the US debate over how the terminally ill Libyan convicted of the 1988 bombing of a Pan Am flight was allowed to return home "may come up" but is not a "major issue.”
Asked in an interview with BBC television whether the oil giant lobbied to have Libyan intelligence officer Abdel Basset Al-Megrahi released, Cameron replied: "I've no idea what BP did. I'm not responsible for BP."
BP has confirmed it lobbied the British government in late 2007 over a prisoner transfer agreement with Libya but said it was not involved in talks on the release of Al-Megrahi.
There is no evidence BP was involved in his release or that the decision to free him was made to facilitate oil deals for BP, British Foreign Secretary William Hague said last week.
Cameron said that as the opposition leader at the time he thought the release decision was "completely and utterly wrong.”
He said he was convicted "of being the biggest mass murderer in British history. I saw no case for releasing him from prison and I said that a year ago, remember, a year ago when we were all told, of course, he had only two months to live."
Megrahi remains alive today.
A spokesman for Cameron said the focus of the US trip would be on "the big issues on which we have a strong common agenda: Afghanistan, the global economy and the Middle East.”
Cameron, in power since May, has said he will stand up for BP in Washington, worried that the firm could face unreasonable compensation claims from businesses and families affected by the worst oil spill in US history.
The BP saga and concerns the US has decoupled from Europe in its approach to economic policy at an important juncture for the global recovery will test Cameron's aptitude for diplomacy.
British leaders have long treasured a "special relationship" with the United States, which has helped the smaller country punch above its weight on the global stage. Cameron, an outspoken fan of the American way of life, will be no different.
His new Conservative-Liberal Democrat coalition government is aware Britain needs to build other special ties to maintain its influence and help its economy bounce back from recession.
"I think this is a government that is cautious about being seen as being in America's pocket or being instinctively and automatically a follower," said Robin Niblett, director of the Chatham House think tank.
A Cameron trip to India with several business leaders due after the US visit will underline the importance Britain is placing on emerging markets for future trade.
Cameron will pitch for business during meetings with industry leaders in New York on Wednesday, conscious that an increase in British exports is important for recovery at home.
In Washington, Afghanistan will dominate several of Cameron's meetings. Britain wants to pull its troops out of Afghanistan within five years, an announcement that has raised some eyebrows in military circles.
Talks at the White House and the Pentagon on Tuesday and Wednesday, coinciding with an international conference in Kabul, could address how realistic that timetable is given the slow progress made in improving security on the ground.
"This will be a good opportunity for the leaders to take stock of progress in this vital year," Cameron's spokesman said.
Fiscal policy differences between Europe and the United States will also come under the spotlight.
Britain leads European attempts to cut budget deficits which have ballooned in the wake of the global financial crisis, while the United States has urged caution.
Officials say both sides have agreed to disagree on fiscal policy for now but markets remain nervous over the health of the US economy — the world's biggest — and analysts say reducing borrowing too fast could hinder the fragile global recovery.
