Cabinet minister Ken Clarke has warned Eurosceptics that they risk wrecking the prospect of the UK benefiting from a proposed trade deal with the United States.
David Cameron has hailed the possibility of the "biggest bilateral trade deal in history" as the US and European Union launched negotiations on a comprehensive transatlantic agreement.
Mr Clarke, one of the most pro-European Conservatives, warned that it would be "curtains" for the UK's ability to play a leading role if the country left the EU.
Minister without portfolio Mr Clarke wrote in the Daily Telegraph that it was the UK's membership of the EU that made it a key player in negotiations with Barack Obama's administration in Washington and cautioned against demands for "Brexit" - a British exit from the organisation.
He said: "It is of course the EU that is making deals with America and Canada possible. It should come as no surprise that president Obama's officials have commented that they would have 'very little appetite' for a deal with the British alone.
"Quite simply, the political commitment and dedication that the creation of a free market encompassing over 800 million people, 47% of world GDP, and boosting the combined economies of the EU and the US by nearly £180 billion, could only ever be made by the leaders of evenly matched economic blocs."
Mr Clarke said despite the "romantic" notion of the UK leaving the EU and joining the North American Free Trade Agreement, Britons were "a practical race".
He said: "That 'Brexit' would mean curtains for our ability to have any leadership role in world-defining plays like these free-trade agreements would greatly disturb us.
"Accepting a diminished situation in which the UK is forced to trade by EU rules which it has had no say in setting is simply not in our nature.
"That is why there was such admiration for the European role that Mrs Thatcher played as PM: handbag swinging, never giving in, never giving up, she alternately charmed and cajoled Europe into the reforms which she saw were so clearly needed."
He said the trade deals being championed by Mr Cameron were "positively Thatcherite" and praised his efforts to reform the EU to make it "an ever greater asset".
"Because an asset it undoubtedly is," Mr Clarke said. "The European Union amplifies our influence in the world, renders us safer, more secure, and more in control of our own destiny.
"As Germany shows, the EU can indeed be the home of powerhouse exporters who dominate global trade. The place for a powerful nation state in the world of today and tomorrow is within it, not outside it - even more so than in the 90s, when the economic giants of the East were still emerging.
"There remains an undoubted need for serious further European reform. The doom-mongers who say this will never be achieved should remember that a European-North Atlantic Free Trade Area was talked of as an unachievable dream for at least two decades.
"British leadership and lobbying means it really now could be a reality. There is plenty more that we can achieve in Europe. We must stay the course."