David Cameron has been warned that ministers will resign unless they are allowed to campaign to leave the EU.
Veteran Eurosceptic John Redwood said ministers must be allowed to campaign "as they see fit" in the in/out EU referendum expected by the end of 2017.
Europhile Ken Clarke also said they should be allowed a free hand.
The PM has made it clear he will expect ministers to back a "yes" vote if he recommends the country accepts his re-negotiation of Britain's membership.
Asked about the issue on Sky News, Mr Redwood said: "Of course they should be free to campaign as they see fit and they will be free to campaign as they see fit.
"The only issue is whether they are asked to leave their government positions before they do it or not."
The Conservative MP claimed there would be no risk to jobs and trade if Britain left the EU because the trading bloc needed to remain on good terms with the UK.
He told Sky News he wants Britain to come out of the "current EU" but would support Mr Cameron if he gets a "really good deal" in renegotiation.
Ken Clarke, a longstanding advocate of Britain's membership of the EU, also urged Mr Cameron to allow ministers to campaign for the "no" side if they wanted to.
He told BBC One's Sunday Politics the referendum was meant to allow people to solve their differences on Europe in a "civilised way," adding: "I would let the Eurosceptics have a kind of free exercise in campaigning in the referendum."
He dismissed demands by Conservative Eurosceptics like former defence secretary Liam Fox for Mr Cameron to seek the repatriation of powers from Brussels as part of his re-negotiation.
"He (Cameron) is not asking to repatriate any powers," he said.
"Most of the people demanding the repatriation of powers can't think of any or want to repatriate powers that would lead, for example, to an inability to tackle international crime."
He said he was in favour of an early referendum, amid speculation one could be held next year.
"If we let if drift on this daft debate will continue and it really does actually cause a great deal of uncertainty," said the Tory MP.
There has also been some debate who should lead the official Yes and No campaigns.
Mr Clarke ruled himself out and said it should be someone younger who could command cross-party support but he was hoping to play a role in the referendum through a pro-EU pressure group called British Influence.
Labour's Frank Field, who is in favour of Britain's exit, said it should be someone who is young enough not to have taken part in the 1975 EU referendum, when Britain voted to stay in.
But UKIP MP Douglas Carswell suggested a business leader such as Sir James Dyson, 68, who was a "wealth creator," should head up the campaign to come out.
He stressed that the "really important thing" was that the case for leaving the EU was "made in a really positive way".
In a separate development, former president of the European Commission Jose Manuel Barroso said it would be difficult for David Cameron to get "important change" without reopening EU treaties, something that is resisted by France, Poland and other countries.