SOUTHAMPTON, Bermuda, Oct 24, 2012 (AFP) - Harrington, a three-time major winner, lost out in playoffs in this event in 2007 and 2008.
His third attempt saw him playing as an alternate in the tournament designed for the year's four Grand Slam champions, filling in for British Open champion Ernie Els, who withdrew with a mild ankle sprain.
Harrington birdied three holes in a row starting at the 11th to pull away and finished with a nine-under total of 133 to claim the $600,000 first prize.
The Irishman's most recent victory was at the Asian Tour's Johor Open in 2010.
"We haven't had a win in a long time and I've got to tell you, they don't come around anywhere near as often as you believe they come," Harrington said.
"When you win, you make sure you enjoy it. And it was unfinished business for me, having lost in two playoffs. It's nice to come back and win it now. It feels good. I haven't won in a while."
Simpson posted a 67 without a bogey to finish second on 134, saying Harrington's back-nine birdie run was the critical moment.
"I had some good looks and played them even and he played them 3-under," Simpson said. "I had two putts I hit in a row that were a foot out. The ball is in the middle and you think it's going to stay straight. Kind of gut-wrenching."
Masters champion Bubba Watson carded a 71 and former PGA Championship winner Keegan Bradley a 67 to share third on 139.
Bradley, who won this event last year, was filling in for reigning PGA Championship title holder Rory McIlroy, who withdrew to play a European Tour event in China.