Tory former cabinet minister Liam Fox has urged David Cameron to "end the pretence" on EU renegotiation and back Britain's exit.
Dr Fox said 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.
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 on Britain's membership 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.
But writing in the Sunday Times, his former defence secretary said that none of the changes he was seeking were "a reason to stay in an organisation whose direction of travel is against Britain's national interest".
The intervention was said to have been at the request of ministers becoming increasingly unhappy with the renegotiation.
"The renegotiation itself reinforces this view. What we have seen is the process becoming the narrative.
"The fact that a British prime minister has been effectively forced to take the political begging bowl around European capitals in order to make the laws that he believes necessary for Britain is the best possible demonstration of the problem," Dr Fox wrote.
He said: "Ever since I entered parliament 23 years ago I have been told that 'Europe is coming in our direction'. It is time to end the pretence. It is not.
"The talk at the recent summit may have been about accommodating Britain's reservations about the over centralising of powers but the action is going in exactly the opposite direction. It always has and it always will."
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.
Dr Fox warned that both sides of the debate needed to show respect if the Conservative Party was not to tear itself apart.
"Those who wish to remain in the EU are not 'unpatriotic' and those who wish to leave are not 'idiots', he wrote.
"Treating the views of others with respect, important in itself, will be key to our ability to govern effectively for the rest of the decade. It is important, however, for people to understand that there will be no risk-free option at the referendum."
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.
Tough negotiations remain to be had over his push to curb the flow of EU migrants to the UK, with many leaders firmly opposed to the proposal to prevent them claiming in-work benefits for four years.
"I believe if we can get these reforms right - and I believe that we can - I firmly believe that for our economic security and increasingly for our national security, the best future for Britain is in a reformed European Union," he said.
Former Marks & Spencer chief Sir Stuart Rose, who is chairman of the "remain" campaign group, accused those campaigning for Brexit of failing to make the case.
"They cannot answer basic but fundamental questions on how the economic benefits of being in Europe could be replicated, let alone improved upon, on the outside," he wrote in a letter to the newspaper.
"You cannot have the benefits with none of the costs. Whether they haven't realised this or won't admit it, the damage of being outside the world's largest free trade zone would be very real."
Dr Fox downplayed suggestions his intervention signalled any intent to position himself for another shot at the party leadership.
"People should not read anything into it other than it's what I believe and I'm prepared to do what I believe rather than wait and hide," he said.