Senior Conservative MP and London mayor Boris Johnson is due to announce later which side he will back in the EU referendum vote, and is widely expected to campaign for the UK to leave.
It comes as ministers began campaigning on the UK's EU membership, after the PM called a referendum for 23 June.
The BBC's Norman Smith said Mr Johnson, previously thought to have been "conflicted", had now made up his mind.
The MP is expected to reveal his decision at 22:00 GMT.
He will give the reasons in his column for the Telegraph newspaper later, according to a count-down on the paper's website.
The BBC's political editor, Laura Kuenssberg, said it would be a "big blow" to Number 10.
But she said Downing Street had been resigned to Mr Johnson campaigning to leave following a meeting this week which left him disappointed with Mr Cameron's plans on the EU.
The Conservative candidate to be the next mayor of London, Zac Goldsmith, will also vote to leave the EU, his team has confirmed.
Mr Cameron has said he will campaign to remain in a "reformed" EU, but six ministers who attend cabinet have joined the leave campaign.
Asked on the BBC's Andrew Marr Show if he wished to send a message to Mr Johnson, the prime minister said he would "say to Boris what I say to everybody else".
"We will be safer, we'll be stronger, we'll be better off inside the EU.
"If Boris and if others really care about being able to get things done in our world, then the EU is one of the ways in which we get them done."
Referring to two other prominent supporters of the leave campaign, Mr Cameron also warned against "linking arms with Nigel Farage and George Galloway".
Earlier on the Marr Show, UKIP leader Mr Farage said he would "absolutely" like to see Mr Johnson come out in favour of leaving the EU.
"He's one of those half a dozen people that reaches out to a large number of voters. We'd love to see 'Bo Go' as the headline tomorrow."
Mr Johnson's sister, the writer Rachel Johnson, told Sky News's Murnaghan programme that her brother was not "milking his decision for maximum publicity".
She said: "It's a very, very hard choice that he has to make. It's a hard choice for everybody to make, because there are good and bad arguments on both sides."
Asked if he was "on the horns of a dilemma", she agreed, saying it was "agonising" for him.
Ms Johnson's refusal to give away what her brother might have decided led the Sun's Westminster correspondent, Harry Cole, to tweet about her "poker face".
House of Commons leader Chris Grayling told the BBC's Sunday Politics programme that he hoped Mr Johnson would join the campaign to leave the EU, adding: "I know no more about his intentions than anyone else."
Mr Johnson has also discussed the referendum with Justice Secretary Michael Gove, one of those to declare support for the leave campaign.
The Sunday Times reported that Mr Johnson, thought to have been undecided earlier, had told a Westminster colleague: "I'm veering all over the place like a shopping trolley."