Walsham, an Australian who lives in Singapore, climbed 86 flights of stairs in 11 minutes, 57 seconds. Thorbjorn Ludvigsen, of Norway, won the men's race in 10:06.
"That was a goal of mine coming here. No other female has won it more than four times and I wanted to be the first," said Walsham, 40.
Ludvigsen, 25, came in second at last year's race and said winning "feels great."
"It's been one of my goals," he said, clutching a trophy in the shape of the iconic skyscraper.
Runners from around the world took part in the vertical dash up 1,576 steps, starting at the lobby and finishing on the 86th floor. The event - among the more high-profile tower climbs in the world - usually ends on the observation deck, but the poor weather brought the finish line inside. Five hundred people were registered to take part.
Devang Patel, 24, was in the open field, running in his second tower climb. The North Bergen, N.J., resident said the challenge appealed to him, as someone who has run marathons.
"This is much shorter, but you still feel the pain," he said.
Lynda Hubbard, 42, was running in her ninth climb after giving birth seven months ago. She encouraged others to give it a try.
"To be part of something like this, all these people, is just amazing," she said. "Anyone can do it, if they just put their minds to it."
The event was put on by the New York Road Runners, which also puts on the annual New York City Marathon.
Like the marathon, start times were staggered. The elite men and women started before the general field, and those in the general field were sent up in seconds-apart intervals, a tactic put in place to avoid crushes of people trying to get into the stairwell at the same moment.
Darren Wilson, of Australia, finished second in the men's race with a time of 10:21, and Erika Aklufi, of Los Angeles, finished second in the women's race in 12:48. Seven-time men's champion Thomas Dold, of Germany, did not race this year.