The 41-year-old Dubliner, who lost play-offs at Mid-Ocean in 2007 and 2008, started with a five-under-par 66 at Port Royal to lead Masters champion Bubba Watson by two, US Open winner Webb Simpson by three and holder Keegan Bradley, Rory McIlroy's replacement, by six.
The event is meant to be between the year's four major winners, but with McIlroy opting to play in Shanghai, Ernie Els pulling out with an ankle injury and reserves Graeme McDowell and Tiger Woods turning it down - they are in Asia as well - Harrington received a call.
Eighth behind Watson at Augusta and fourth to Simpson in San Francisco, he grabbed seven birdies and would have been even more in control but for bogeys at the third and 16th, both par threes.
Simpson came back into the picture with three back-nine birdies but then bogeyed the 431-yard last while left-hander Watson, his Ryder Cup partner, mixed an eagle and five birdies with four bogeys.
Bradley, who last year beat McIlroy, Darren Clarke and Charl Schwartzel, was always fighting an uphill battle from the time he double-bogeyed the fourth and bogeyed the next two to stand four over.
Even the player who finishes last still earns £125,000.
Harrington said: "We were all very relaxed out there - everybody was up for a chat and I play better when the whole group enjoys it.
"If the guys have any sense they shouldn't talk to me tomorrow [Wednesday].
"I'm probably just a little bit lucky that there wasn't too much wind. There wasn't a lot of local knowledge, but if we got a change of wind direction that would be very awkward for myself, Bubba and Webb." Bradley won on the same course last year.
Watson said: "I had a couple of tough shots out there and a few three putts, but three under I can't get too mad at that.
"There's probably about four holes where you hit a drive as far as you can, but then it rolls back, so that means length is not an advantage on this golf course. It's about solid iron shots and making putts."
Bradley commented: "I've been six shots back before with less time, so I look forward to going out and just making a million birdies. Padraig played great today [Tuesday] and if he plays the way he did I have no chance."