The former Conservative Chancellor, Lord Lawson, has significantly widened the deep fracture within the Tory party over the toxic issue of Europe.
In an explosive intervention he piled the pressure on the Prime Minister saying it was time to quit the EU and any concessions Mr Cameron could negotiate would be 'negligible'.
ITV News political editor Tom Bradby reports:
Lord Lawson became the most senior Tory figure to call for the UK to quit the European Union - pledging to vote No in any referendum on membership.
In a move that piles further pressure on David Cameron over the issue, the former chancellor warned the Prime Minister's proposed renegotiation would only secure "inconsequential" concessions from Brussels.
Writing in The Times (£), he said there was now a "clear" case for withdrawal, insisting the economic benefits would "substantially outweigh the costs", in contrast to the Prime Minister's position.
His intervention is sure to further embolden eurosceptic MPs demanding a tougher line to halt the rise of Nigel Farage's rampant anti-EU UK Independence Party (Ukip).
Mr Cameron is already under pressure to hold a "mandate referendum" as early as next spring to seek public approval of his strategy of putting a renegotiated settlement to an in/out vote by 2017.
In the wake of Ukip's surge in last week's county council elections, there is also pressure to put the strategy to a vote in the Commons in defiance of his Liberal Democrat coalition partners.
Lord Lawson, who was Margaret Thatcher's longest-serving chancellor and remains a highly-respected figure within the party, said that it was "by no means assured" that Mr Cameron would win the 2015 general election.
But he said he believed public demand was such that a referendum would have to happen under Labour in any case.
Dismissing the chances of either party securing significant reforms, he said Brussels would fear a "general unravelling" as other countries sought to match the return of powers.
While there would be "some economic cost" from leaving the EU single market, he went on, "in my judgment the economic gains would substantially outweigh the costs.
Quitting the single market would only have "marginal" disadvantages, he suggested, and could even have "a positive economic advantage to the UK" by forcing British firms to look further afield.
Too much UK business and industry felt "secure in the warm embrace of the European single market and is failing to recognise that today's great export opportunities lie in the developing world", the peer wrote.
Richard Edgar reports on how the issue is dividing British businesses: