Alfredsson matched her first round of 67 for a 10-under 134, one stroke ahead of Sophie Gustafson, who shot 68.
Three strokes back of Alfredsson in third place at 137 are Paula Creamer (68) and Kelli Kuehne (70).
Lorena Ochoa and first-round leader Angela Park are in a group five shots back, and Annika Sorenstam rebounded from a first-round 72 to shoot 68, putting her among nine players at 140.
Alfredsson, who won for the first time since 2003 in July at the Evian Masters, has earned $961,817 in 2008, more than double her previous best season. Alfredsson will climb over $1 million in earnings this season should she finish eighth or better in the Safeway.
She made six birdies ' four on the front nine and three with putts of 7 feet or less ' and one bogey in the second round. Alfredsson finished her round by holing a 15-foot birdie putt at the par-4, 383-yard 18th.
She made her only bogey of the tournament at the par-5, 462-yard seventh, though it was unconventional. Alfredsson drove her tee shot out of bounds, then used her next two shots to get to within 3 feet of the hole. She missed the putt, and settled for a bogey.
Gustafson reached as low as 11-under until she made back-to-back bogeys at 16 and 17, her first two of the tournament. She ran off a string of four consecutive birdies early in the round on the way to recording a 4-under 32 on the front nine.
The cut was even-par 144. Among those failing to qualify for Sundays final round include Rookie of the Year points leader Yani Tseng (145) and Se Ri Pak (150).
First prize in the the $1.7 million Safeway Classic, the longest running non-major on the LPGA Tour, is $255,000.