Kaymer made six birdies as he set the lowest score in three Opens held at Pinehurst number two.
He one-putted the last five holes, including a six-foot par putt on the 18th that gave him a five-under 65 and a three-shot lead.
So much was made of the new look at number two, which was restored to its old look from more than a half-century ago.
I put myself so far in a good position, but we have three rounds to go and the golf course can change a lot.
Former US Open champion Graeme McDowell took the conservative route on his way to a 68 that featured 15 pars, one bogey, one birdie and one eagle.
He was joined by Kevin Na, Brendon de Jonge and Fran Quinn, a 49-year-old who last played a US Open in 1996, when Tiger Woods was still an amateur.
Brandt Snedeker, who had a chance at 30 on his front nine, had to settle for being part of a large group at 69 that included 20-year-old Jordan Spieth, Henrik Stenson, Matt Kuchar and Dustin Johnson.
Phil Mickelson, in his latest quest to win the one major keeping him from the career Grand Slam, shot a 70. He was among the early starters, who received additional help by cloud cover that kept moisture in the greens.
Masters champion Bubba Watson was among the exceptions. He shot a 76 and said, "This course is better than me right now."
The sun broke through shortly before noon and began to bake the course, though not enough to stop Kaymer.
Defending champion struggles
Defending champion Justin Rose had a 72, making his bid a little tougher to become the first repeat winner in 25 years. Adam Scott, the world number one who has been formidable in every major the last two years except the US Open, had a 73.
Kaymer picked up four birdies with relative ease with three wedges to inside three feet, and a high draw with a three-wood to about 20 feet on the par-five fifth for a two-putt birdie.
"I wasn't expecting it. I'm not freaking out about it," he said. "It's the first round of a very, very important tournament. I put myself so far in a good position, but we have three rounds to go and the golf course can change a lot."
Kaymer tied the course record with a 63 in the opening round when he won The Players Championship last month, ending a drought of some 18 months.