The American, who revealed he has been suffering from back pain, opened up a two-shot lead over Scotland’s Russell Knox at the halfway stage of the Shanghai showpiece with his two-day total of 14-under-par 130.
Overnight leader Branden Grace of South Africa signed for a 71 to take third place ahead of China’s Li Hao-tong and Patrick Reed of the United States at the Sheshan International Golf Club.
Australia’s Scott Hend, second on the Asian Tour Order of Merit, remained in the hunt for his first World Golf Championship after he added a 69 to his first round 68 to take a share of ninth place.
Kisner, who is making his debut in the tournament after gaining a late spot in the field having been seventh reserve, picked up two shots over the last three holes after an impressive outward 32 to take his place atop the leaderboard.
"It's beyond my expectations. I had no expectations coming in so it's been good. I'm making a lot of putts and that's fun keeping the round going when I miss a green,” said the American.
While he was happy with his flawless 66, the 31-year-old is hoping his back pain will ease as he heads into the weekend rounds in a commanding position.
"It's not like an injury where it's going to get worse. It's just dealing with the pain, and it's gotten better every day, so hopefully this weekend it will be perfect," said Kisner.
Hend also powered his way up the leaderboard to stay within sights of the leaders. The big-hitting Australian enjoyed another day out at the Sheshan International Golf Club but had his card spoilt by a lone bogey on the par-five second.
“I’ll keep doing the same over the next two days. The only thing unfortunate today was on the second hole where I hit the ball into the water.
“I hit my tee shot into the wind and it was not able to carry itself over the water. But other than that, it was a solid day and it was good,” said Hend.
World Number Two Jordan Spieth meanwhile needed a birdie on the last to save his round after a run of three bogeys from 11 had threatened to derail it.
Spieth shared 27th place with nine other players that included Thailand’s Thongchai Jaidee and world number three Rory McIlroy of Northern Ireland.
“I lost a lot of focus there and I felt like I wasn't zeroing in. I felt like I was very lazy in my routine, very lazy in picking targets. And it bit me with three unforced errors in a row on the back nine there.
But I’m pleased with the way that I bounced back got two more coming in. Because it looked like I could have just bogeyed in,” said Spieth.
Hend is the leading Australian although his fellow countryman who many though might contend this week, Adam Scott, is running a distant second last at this stage.
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