In an article for The Sunday Telegraph, he acknowledged that the country's position within an evolving European Union must have "the full-hearted support of the British people".
But he insisted that the vast majority of the public did not support an immediate referendum on whether Britain should be in or out.
Nearly 100 Conservative MPs have written to Mr Cameron urging him to make it a legal commitment to hold a poll on the EU during the next parliament but Mr Cameron was cautious about how the issue would be put to people.
He said: "There is more to come - further moves, probably further treaties - where we can take forward our interests, safeguard the single market and stay out of a federal Europe.
"How do we take the British people with us on this difficult and complicated journey? How do we avoid the wrong paths of either meekly accepting the status quo or giving up altogether and preparing to leave?
"It will undoubtedly be hard going, but taking the right path in politics often is.
"As we get closer to the end point we will need to consider how best to get the full-hearted support of the British people, whether it is in a general election or a referendum.
"As I have said, for me the two words 'Europe' and 'referendum' can go together, particularly if we really are proposing a change in how our country is governed, but let us get the people a real choice first."
Shadow foreign secretary Douglas Alexander told Sky News: "It's extraordinary. In the space of 24 hours we had the Telegraph saying the prime minister had ruled a referendum out and now he's ruled one in. It's a shambles.
"What we've heard from the Foreign Secretary William Hague this morning is that there's no change in the government position.
"At least they're now sending out senior government ministers to explain a confused government policy but actually I think what should worry us all is the motivation for the decision doesn't seem to be the future interests of Britain but the present difficulties of the prime minister."
Mr Cameron's article in the newspaper comes after an EU summit called to tackle the eurozone crisis moved the bloc towards closer ties.
After the meeting, he told reporters he was not in favour of an in/out referendum, leading some to believe he was ruling out a popular vote altogether.