Pettersen shot a 4-under-par 68 at the Blackwolf Run course for a two-day total of 5-under 139.
That put her a shot in front of Cristie Kerr and Wie, who missed the cut in five of her previous six stroke-play events. Her best finish of the year has been a tie for 38th at a tournament in Thailand.
Wie shot a 6-under 66, her lowest score of the season and only the second time in 2012 she has broken 70.
Sandra Gal, Inbee Park and Vicky Hurst shared fourth place at 3-under 141. Lizette Salas and Mika Miyazato were at 142.
Lexi Thompson, who five years ago became the youngest player ever to qualify for this major championship when she did so at the age of 12, missed a chance to challenge for the lead.
After opening the tournament with a 70, Thompson made five birdies during the second round. But she also suffered three double bogeys and wound up shooting a 73 that left her four shots out of the lead in a tie for ninth.
World No. 1 Yani Tseng made three late bogeys and had to settle for a 72 that put her at 146, tied for 29th.
Swim Week Miami Beach 2014 [PHOTOS]