Conservative Party veteran Ken Clarke has warned a "no" vote in David Cameron's promised referendum on European Union membership could be a "fatal mistake".
Mr Clarke, the Minister without Portfolio, said it was essential to focus on the "positive things" Europe had to offer "and not just the things we are against".
The Prime Minister said last week he would renegotiate Britain's relationship with the EU and then put the result to a popular vote if Conservatives won the next general election in 2015.
The move was widely welcomed by Tory Eurosceptics but criticised by other EU leaders.
Mr Clarke was by joined former Labour cabinet minister Lord Mandelson and Lib Dem Treasury Secretary Danny Alexander as he launched an impassioned defence of Britain's place in the Europe.
Speaking at the launch of the cross-party Centre for British Influence campaign Mr Clarke said: "There is a huge potential prize out there for the United Kingdom if only we focus our attention and influence in any future negotiations on the positive things that really matter.
"We need to concentrate on what we are in favour of and not just what we are against. It is in our vital national interest that we avoid the fatal mistake that would be a 'no' vote if a referendum is held in the next few years."
Lord Mandelson accused opponents of the EU of putting out "lies and false propaganda", and called for an end to the "mindless, inward looking, soul-searching and navel-gazing" over Britain's place in the group.
"For far too long, those who want to destroy Britain's interests and influence in Europe have been allowed to get away with murder with the lies and false propaganda they have poured out about the European Union and what it represents for our country. This cannot go unchallenged anymore," he said.
Mr Alexander dismissed suggestions the UK could rid itself of the bulk its EU obligations as "nonsensical". "We cannot afford to give the impression that we are going to disengage," he said.
Earlier, opening a Commons debate on Europe, Foreign Secretary William Hague vigorously defended Mr Cameron's referendum plan.
"It's our responsibility as one of the leading members of the EU to press for reforms that must happen if the EU is to succeed in this century; more competitiveness, flexibility, democratic accountability and fairness for countries both in the eurozone and outside it," he said.
"All those will benefit the UK and the EU as a whole."