Tony Blair warned on Wednesday that it would be "a monumental error of statesmanship" for Britain to turn its back on Europe.
The former prime minister added that David Cameron's policy of renegotiating the UK's position in the European Union would pave the way for withdrawal.
Leaving the EU would be "politically debilitating, economically damaging and hugely destructive of Britain's true long term interests", said Blair.
Speaking to a business audience at the foreign affairs thinktank, Chatham House, in London, Blair said: "Europe is a destiny we will never embrace easily. But it is an absolutely essential part of our nation remaining a world power politically and economically.
"It would be a monumental error of statesmanship to turn our back on it and fall away from a crucial position of power and influence in the 21st century."
Cameron has indicated that he wants to renegotiate the UK's relations with the EU with the prospect of a referendum on the outcome following the general election. But he is resisting pressure from within his own party for an in/out referendum.
Amid speculation that Ed Miliband may be considering committing Labour to an in/out poll, Mr Blair said it was not "sensible" to be talking about a referendum at this point.
"Let's be very clear about this 'renegotiating the terms of membership' line," said Mr Blair.
"This is the refuge of those who want to leave but want to persuade people that it's really just an adjustment of our relationship. Then in the course of the adjustment, when the going gets very rough - as it will - they will then say 'Well it's a pity but now it seems adjustment is not enough'.
"Don't go down this path unless we are prepared to follow it all the way."
While refraining from commenting directly on how Mr Cameron should handle eurosceptics in his own party, Mr Blair made clear he believes some Tories have developed an irrational fixation on withdrawal.
"The right have got it really bad on this Europe thing and it is a kind of virus that makes you want to take positions for the sake of asserting them, when a rational analysis says you don't need to be in that position," he said.