Mickelson made only one bogey and got hot with his irons on the back nine with back-to-back birdies inside 5 feet and a 3-wood from 287 yards that set up an eagle on the 17th hole, sending him to 6-under-par 65 and a chance to win for the second week in a row.
Harrington made only two pars on his first 10 holes, a round filled with brilliance and bogeys, until he finally settled down in the twilight hours off Sunset Boulevard to polish off 68.
Both men were at 11-under 131, three shots clear of Charles Howell, who shot 65.
"Anything in the 60s was really the goal today," said Harrington, playing the Nissan Open for the first time. "I knew going out there I would be a little erratic."
Mickelson hasn't played Riviera since 2001, and he only added the tournament to his schedule at the last minute to test the newfound confidence in his driver. Two rounds in, he hasn't found any flaws.
"I like the way I put the ball in play," Mickelson said. "It feels easy."
He reached all three par-5s in two, none more impressive than the 17th. Coming off his only bogey of the tournament, when he pulled his tee shot into a back bunker on the par-3 16th, Mickelson hit a bullet of a tee shot about 310 yards down the left side of the fairway. He followed that with a hard 3-wood that drew slightly and found the middle of the green, rolling to 15 feet.
"I was just trying to get down there by the green in two," Mickelson said. "I still wanted to be left so I would have a good angle to the green, and I just flushed it. It came off perfect."
It was another command performance, similar to last week at Pebble Beach when he won by five shots. He missed only four fairways, but none of them was off the fairway by much, and he never had a problem going after the flag. The only glitch was a few irons that he pulled, but it only cost him a bogey on the 16th.
The next test comes on the weekend, as Mickelson has made the cut only five times in nine tries at the Nissan Open, and he has never finished in the top 10. Harrington found himself scrambling from the start, three-putting for bogey on No. 10 when he missed a 4-foot putt. But every mistake was followed by birdies on par-3s and good wedge play.
Howell was in the first group off and matched Mickelson for the best score of the day, playing bogey-free for 65 to finish at 134. Howell made four consecutive birdies around the turn.
Howell hasn't won in five years, but he took another step toward ending that drought.
"The best thing I can do is keep giving myself chances," he said.