David Cameron faced pressure to give Eurosceptic ministers licence to campaign for Britain to leave the EU as an MP said opinion within the party was "substantially hardening" against his renegotiation effort.
Steve Baker, of the Conservatives For Britain group, said he believed more than half the Conservative Party "is strongly leaning to 'leave'" and that senior resignations were inevitable if the Cabinet was forced to toe a common line.
Former defence secretary Liam Fox declared that he would vote in favour of "Brexit" whatever new relationship the PM secured from fellow European leaders and urged Mr Cameron to "end the pretence".
But former prime minister Sir John Major gave a robust defence of his successor's push for reforms and called on ministers to present a united front "for the sake of the country" which would be poorer and more dangerous outside the bloc.
Mr Cameron emerged on Friday from a two-day Brussels summit insisting he was "well on the way" to securing "fundamental change" to the relationship on issues like migration benefits.
He gave the clearest signal yet that an in/out referendum would be held next year and that he would lead the "in" campaign, stressing that membership of the reformed EU would be best for the UK's economy and security.
Dr Fox - in an intervention reported to have been made on behalf of frustrated ministers - wrote in the Sunday Times that none of the PM's proposed changes were "a reason to stay in an organisation whose direction of travel is against Britain's national interest".
The sight of the Prime Minister "forced to take the political begging bowl around European capitals" to push for reforms that did not go far enough should persuade people that "Brexit" was the only option, he said.
The newspaper said three cabinet ministers - Iain Duncan Smith, Chris Grayling and Theresa Villiers - were thought to be prepared to resign if Mr Cameron did not allow members of his top team to join the Leave campaign when the referendum is called.
Weekend speculation suggested another potential rebel - London Mayor Boris Johnson - could be offered the role of foreign secretary in a reshuffle in an effort to ensure he campaigned for the "remain" side.
Mr Cameron has promised to hold the public vote before the end of 2017. But a deal at the next European Council summit in February would clear the way for the referendum to be held much earlier, with speculation that his preferred date is June 16.
That has intensified demands for him to make clear whether he will avert potential resignations by allowing ministers to campaign on either side.
Mr Baker told the Sky News Murnaghan programme that the group he co-chairs had 150 MPs signed up to its mailing list.
"What I have seen over the last few weeks is that colleagues are substantially hardening up ... and saying this deal just isn't good enough," he told the Sky News Murnaghan programme.
"I think it is inevitable that some members of the Cabinet will feel they have to resign if they are browbeaten into supporting a deal this flimsy."
Dr Fox said it was "effectively a matter of conscience".
But Sir John - whose said he regretted having to spend "the best part of seven years trying to keep a party at civil war over Europe together" - dismissed "bogus" criticism of Mr Cameron's proposed reforms and appealed for a united front.
"It would be extraordinary if anybody decided to campaign against Cabinet policy, at least until the negotiations are completed," he told BBC One's The Andrew Marr Show.
"When the negotiations are completed, I would very much hope that they would not wish to campaign against.
"This is bigger than the Conservative Party. The argument for the sake of the country is very important. And people deserve to hear a clear-cut argument, not an internecine piece of party strife."
He said he was confident the renegotiation would result in a "very different relationship" between Britain and the EU, including a "common sense" compromise on freedom of movement to deal with the pressure of internal migration.
"The argument that the Eurosceptics have been advancing - since before the Prime Minister set out his aims - that it would be trivial is a good arguing point for them but it is essentially bogus when you look at the detail.
"In fact it embraces many of the things they have been asking for for a very long time."
Dismissing the prospect of a second referendum, he said: "If we vote out then we are out and we will have to get on with it and face the consequences.
"Of course we will survive; we are a big and a powerful nation.
"That's not the point. The point is would we be as safe? No. Would we be as well off? No. Would we be as influential? No."
Dr Fox warned that both sides of the debate needed to show respect if the governing party was not to tear itself apart after the referendum.
"Those who wish to remain in the EU are not 'unpatriotic' and those who wish to leave are not 'idiots', he wrote.
Pro-Europe former cabinet minister Ken Clarke said he agreed but added that "Eurosceptic" was "a euphemism for right-wing nationalism".
"It doesn't mean I don't think that some of them are quite intelligent and sensible and perfectly nice right-wing nationalists," he told Murnaghan.