However, moments after his address to the nation he faced a heavily co-ordinated show of defiance from his own ministers led by Michael Gove, the Justice Secretary, who is also one of Cameron's closest allies.
Gove travelled to the headquarters of the "Vote Leave" campaign alongside Iain Duncan Smith, Chris Grayling, John Whittingdale, Theresa Villiers and Priti Patel. The ministers were photographed with a sign calling for Britain to "take back control".
He then released a 1500-word statement in which he spoke of his "pain" at opposing Cameron but said that the EU was creating "economic misery" and was "built to keep power and control with the elites rather than the people".
He appeared to echo Cameron's "safer, stronger and better off" phrase but instead used the words "freer, fairer and better" to describe why Britain should leave the EU. Villiers, the Northern Ireland Secretary, said "it is time to take back control" and that as long as Britain is beholden to European courts "we cannot say we run our own country".
The so-called "gang of six" are set to be joined by at least 12 junior ministers and more than 100 Conservative MPs.
Cameron will today continue making the case for Britain to stay in the EU and will next week announce plans for a British Bill of Rights designed to ensure that UK sovereignty is guaranteed by "making the Supreme Court supreme".
The swift, unprecedented split came within minutes of Cameron convening a Cabinet meeting. He began with a passionate 20-minute address setting out the deal he secured in Brussels after 30 hours of intense negotiations. He told ministers his deal gave Britain "special status" in the EU and that he would campaign "heart and soul" to remain in the bloc.
He hailed a four-year "emergency brake" of migrants' access to full rates of benefits in the UK that could remain in place for seven years. Cameron also assured his Cabinet that he had secured an opt-out for Britain from future European treaties to "make clear that the references to ever-closer union do not apply to Britain".