He is expected to make the bid official at 5:00 pm (local time) today near his childhood home in Cabot, Pennsylvania where he is to deliver a "special announcement" about his plans.
It will be a more difficult proposition this time around.
With 15 or more prominent Republican presidential contenders as his 2016 rivals, Santorum, 57, is even more the White House underdog than four years ago.
While he has years of new material from which to frame a counterpoint to likely Democratic nominee Hillary Clinton, Santorum has slipped from national prominence, and his appearances draw smaller crowds than the previous cycle.
And he has blasted President Barack Obama's Middle East strategy for lack of leadership, saying the US military must take a dramatically tougher approach to the Islamic State group.
"If these folks want to bring back a seventh century version of Islam, then my recommendation is, let's load our bombers up and bomb them back to the seventh century," Santorum said in a May 9 speech.
He turned his support for blue-collar Americans and conservative Christian values into a surprisingly strong challenge to frontrunner Romney.
His underfunded campaign, prone to the candidate's contrarian outbursts -- he said president John F. Kennedy's speech on church-state separation made him "want to throw up" -- eventually failed, but he lasted longer than anyone expected.
"I ended up competing in 30 states and winning in 11. I was the last person standing," Santorum told a Tea Party gathering in South Carolina in January.
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