This is the first New York City win for Desisa. His winning time was 2:05:59.
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Desisa held off countryman Shura Kitata by 1.99 seconds. Last year's winner, Geoffrey Kamworor of Kenya, finished third.
Desisa also won at the Boston Marathon in 2013 and 2015. He finished second in New York in 2014 and third in 2015 and 2017.
"This is my dream," Desisa said. "To be a champion."
Keitany, with a time of 2:22:48, became the second female ever to win four New York City Marathons.
Keitany beat countrywoman Vivian Cheruiyot by 3 minutes, 13 seconds. American Shalane Flanagan, last year's winner, finished third.
Keitany ran the race in 2:22:48, the second fastest time for the course in history. Margaret Okayo of Kenya set the record of 2:22:31 in 2003.
"I can say the course record was not in my mind," Keitany said. "For me, winning was very important."
First to cross the finish line Sunday morning, in the men's Wheelchair Division, was 20-year-old Daniel Romanchuk.
He is the youngest competitor ever to win a New York City Marathon, with a time of 1:36:21.
Defending champion Manuela Schar of Switzerland won the women's Wheelchair Division with a time of 1:50:27.
The marathon kicked off Sunday morning under clear skies, with more than 50,000 participants taking part.
All four winners of last year's race were back working to defend their titles.
American Shalane Flanagan and Kenyan Geoffrey Kamworor were hoping to repeat, along with Schar and Marcel Hug - both from Switzerland - in the wheelchair division.
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"To be coming back as the defending champion, it's quite an honor and literally a dream come true," said Flanagan, the first U.S. woman to win the NYC Marathon since Miki Gorman in 1977.
Flanagan won in 2 hours, 26 minutes, 53 seconds, beating Keitany.
From 55 runners in 1970, the New York City Marathon has grown to more than 50,000 runners (and 98,000 applicants).
This year's race featured a dominant set of runners from the United States in the women's field, including Flanagan, 2018 Boston Marathon winner Desiree Linden and Molly Huddle.
The men's side included four-time U.S. Olympian Abdi Abdirahman and Shadrack Biwott.
The wheelchair division also featured legends such as Tatyana McFadden.
Heightened security this year included heavy weapons teams from the counter-terrorism bureau as well as plainclothes officers along the course
Results: New York Marathon real-time results
Route: Map and other info
Official race website: TCS New York Marathon
Commuting: Street closures and transit changes
Find Your Finish: Find Your Finish provides a close up look as every runner crosses the finish line
Want to run a marathon? Top running tips to start from the pros!
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(The Associated Press contributed to this report.)
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