Lord Heseltine attacks David Cameron's EU strategy
Lord Heseltine has criticised the prime minister's European strategy, saying an "ill-advised" referendum would jeopardise the UK's business prospects.
The Tory peer also warns the policy would "drive away inward investment".
Mr Cameron is expected to announce this month that the Tories will offer a referendum after the next election.
It is thought he will make the announcement in a speech on the UK's relationship with Europe.
While Lord Heseltine, a former deputy prime minister, is known for being pro-European, many Conservatives are not, and are pressuring the government to commit to a referendum on the question of whether the UK remains in the EU - a so-called "in-out vote".
Lord Heseltine said: "To commit to a referendum about a negotiation that hasn't begun, on a timescale you cannot predict, on an outcome that's unknown, where Britain's appeal as an inward investment market would be the centre of the debate, seems to me like an unnecessary gamble".
He told the Financial Times: "Why put your factory [in Britain] when you don't know - and they can't tell you - the terms upon which you will trade with us in future?"
Mr Cameron has faced pressure to hold a referendum on Europe at some stage during the next Parliament and has been criticised by some in his own party for not doing more to distance the UK from the EU.
He wants the UK to remain within the EU but believes there is a need to redefine the relationship in light of moves towards further integration by countries using the single currency.
Labour leader Ed Miliband said the prime minister should take Mr Heseltine's comments "very seriously".
"It's devastating for the prime minister that you've now got Lord Heseltine saying that he's essentially operating in the party interest, not the national interest.
"If you're an investor thinking about putting your money into Britain, you're not going to be doing that if you think Britain's about to leave the European Union."
UK Independence Party leader Nigel Farage told the BBC that Europe was not essential for British business.
"Outside the European Union, there are nearly 50 trade agreements that the EU has with other parts of the world. They are not bound by the rules, they are not part of that union, that is how business operates.
"We're living in a global economy, and important as Europe is as a marketplace, it is now down to 38% of our exports, and likely to fall further. The UKIP argument is we must embrace the rest of the world for trade, not just Europe."
Lib Dem peer Lord Oakeshott said he was not in favour of having referendums "on fundamental decisions that have already been taken".
He added: "The Conservatives can't have it both ways. If they want to come out of Europe... they should come out and say so. They should stop playing this referendum game which is a way of covering up their own deficiencies."
Senior Conservative backbencher Bill Cash told BBC Radio 4's Today programme that the UK would be edging towards leaving the EU "if things continue the way they are".
He said proposals for the EU's future were "moving in the direction which is completely unacceptable to the British people".
Gunther Kirchbaum, who chairs the European affairs committee of Germany's Bundestag, said: "I'm deeply convinced that to get out of the European Union would also mean to lose influence. Businessmen in Britain are really concerned."
In recent days senior politicians in the US and Germany have warned against Britain leaving the EU, while the leader of the Conservatives in the European Parliament, Richard Ashworth, warned that the UK appeared to be "snarling like a sort of pitbull across the English Channel".
On Friday, Chancellor George Osborne suggested in the German newspaper Die Welt that the UK may leave the EU if Brussels failed to reform.