The two former Prime Ministers, both of whom were heavily involved in the Northern Ireland peace process, will today warned that leaving the EU "jeopardise the unity" of the UK, putting at risk the stability that has built up over time.
But those on the Leave side of the campaign have said that Brexit wouldn't risk destabilising Northern Ireland.
Northern Ireland secretary Theresa Villiers, who is campaigning for a Brexit vote, has said the peace process is "rock solid".
Blair argued that Northern Ireland's prosperity could take a hit: "We understand that, although today Northern Ireland is more stable and more prosperous than ever, that stability is poised on carefully constructed foundations. And so we are naturally concerned at the prospect of anything that could put those foundations at risk."
Meanwhile, Major said that Brexit would risk "destabilising the complicated and multi-layered constitutional settlement that underpins stability in Northern Ireland".
Villiers said: "The vast majority of people in Northern Ireland believe their future should only ever be determined by democracy and consent and not by violence. I very much hope figures who played such an important role in the peace process would not suggest that a Brexit vote would weaken that resolve in any way.
"Whatever the result of the referendum, Northern Ireland is not going back to the troubles of its past and to suggest otherwise would be highly irresponsible."
Northern Ireland has received €3.5bn (£2.7bn) over seven years (2007-2013) in EU subsidies, the majority for farming, according to data from the European Commission. Another €3.5bn is allocated for 2014-2020.
Sinn Fein has also called for reunification if the UK votes for Brexit, with Martin McGuinness pushing for a referendum on the issue.
Meanwhile, George Osborne was in Scotland today, another country in the UK that could demand a referendum if the UK votes to leave the 28-member bloc.
On a lighter note, here's one of the best clips of Blair versus Major in the Commons: