Keflezighi, who was born in Eritrea but is now a US citizen, pulled ahead of a pack of elite African runners a little more than halfway into the race and held off a late challenge by Kenya's Wilson Chebet. His official time: two hours, eight minutes and 37 seconds.
Keflezighi said he had been extra motivated to win after seeing the attack last year.
"It was not just about me. ... I was going to give everything I could for the people," said Keflezighi, a resident of San Diego.
Noting that the Boston Red Sox's World Series championship last year had lifted the city's spirits, he added that he wanted to provide a similar boost: "When the Red Sox did it, I said, 'I want to do it for Boston.'
"This is probably the most meaningful victory for an American, just because of what happened here last year. Up till now I'd say my career was 99.9 per cent fulfilled. Today I'd say it is 110 per cent fulfilled."
Three people, including an 8-year-old boy, were killed and 264 were hurt when, prosecutors say, a pair of ethnic Chechen brothers left homemade bombs at the crowded finish line, tearing through the crowd.
Fans had packed the course, waving American flags and wearing T-shirts bearing the "Boston Strong" motto the city adopted as a rallying cry after last year's attack. Their screams grew deafening as Keflezighi tore through the final miles.
"It is very symbolic that an American won this race today one year after the bombing, said Veronica Carroll, who had traveled from New Jersey to watch her husband run. "It represents the strength of our country."
Some 35,755 runners from 96 countries competed in the second-largest field in history for the 118th running of the Boston Marathon.
Wilson Chebet of Kenya finished second and Frankline Chepkwony, also of Kenya, was third.
No American athlete has stood atop the podium on Boston's Boylston Street, not far from the site of last year's bombing, since 1985 when Lisa Larsen-Weidenbach of Michigan won the women's race. The drought has been longer for U.S. men: Greg Meyer of Massachusetts won in 1983.
Race organizers expanded the field by some 9,000 runners this year, to allow the roughly 5,000 athletes who had been left on the course last year when the twin pressure-cooker bombs went off near the finish line another chance to compete.
One of the two brothers who are accused of the bombing died after a shootout with police a few days after the blasts while the other, 20-year-old Dzhokhar Tsarnaev, is awaiting trial. If convicted, he may face execution.
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