His 10-under-par-130 total topped Camilo Villegas' 36-hole record from last year by three shots. Isenhour is not concerned about records. He wants to win for the first time since the 2003 BMW Charity Pro-Am at the Cliffs.
'It helps to have been there before,' said Isenhour, who also captured the Mississippi Gulf Coast Open in 2000. 'It's been a while. I'm better now than I was then.'
Nationwide Tour rookie Parker McLachlin tallied his second,4-under 66 in as many days and is alone in second place at 8-under-par 132.
Brenden Pappas (66) and Mario Tiziani (67) share third place at minus-7.
Isenhour began his second round on the back nine. He parred his first two holes, then two-putted for birdie from 15 feet at the par-5 12th.
The two-time winner on the Nationwide Tour rolled in a 12-footer for birdie at the 14th. Isenhour made it two in a row when he knocked a 9-iron to 3 feet to set up birdie at No. 15.
Isenhour parred six holes around the turn, but got to 11 under par for the championship at the par-5 fourth. Again he had a good look at eagle, but, like on 12, he missed the eagle putt and tapped in for birdie.
Isenhour stumbled to his only miscue of the round at the fifth. His approach landed 60 feet from the hole and his birdie try came up 15 feet short. Isenhour missed the par putt to fall to 10 under par.
It would not matter as the 37-year-old took the 36-hole lead for the second time on the Nationwide Tour. The last time came in 2000 and he tied for eighth at the Inland Empire Open, but Isenhour feels better prepared to return to the winner's circle.
'I have confidence that I can hit shots I want to under tough conditions,' said Isenhour, who fell apart on the back nine of the final round of PGA Tour Q-school and missed his card. 'I like my chances because I'm out in front and playing well.'
Travis Perkins (64) and Jeremy Anderson (68) are tied for fifth place at 6-under-par 134. Kevin Gessino-Kraft matched Isenhour's mark from Thursday with a 63. He is tied for seventh place with Scott Petersen (65) and Ben Bates (66) at minus-5.
David Hearn shot a 69 on Friday and is alone in 10th place at 4-under-par 136.
The 36-hole cut fell at 2-over-par 142 with 69 players advancing to the weekend.