In addition to McFadden's seventh straight Chicago Marathon win - eighth overall - in a course-record time of 1:39:15, an American won the men's marathon for the first time since 2002.
Rupp, 31, was the first American man to win the Chicago Marathon since Morocco-born Khalid Khannouchi in 2002.
Rupp surged ahead for good with three miles remaining to win in 2hrs 9mins 20secs with Kenyan runner-up Abel Kirui, the defending champion, 28 seconds back and Bernard Kipyego, also of Kenya, third in 2:10:23.
It made Rupp the first home victor since Moroccan-born Khalid Khannouchi in 2002 and the first American-born champion since Greg Meyer in 1982. Last year's victor Abel Kirui of Kenya was placed second while marathon record holder Dennis Kimetto did not finish. "I've made the mistake in the past of going too hard, too soon..." Dibaba was out in front on her own, having gapped Kosgei, while Kirui, Rupp and Ethiopian Sisay Lemma were in contention duking out who would finish where on the men's podium.More news: DC United's Chris Durkin scores for USA at Under-17 World Cup
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"I really wanted to wait", Rupp said. "When I went I knew I had to put the hammer down, be decisive and go for the finish". American Jordan Hasay set a PB finishing third overall, matching her placing-performance from Boston, running 2:20:57.
But ultimately she came up slightly short of the course record. Tirunesh Dibaba of Ehtiopia was the women's victor, finishing in 2:18:30. The Kenyan fell back with 10km remaining, leaving Dibaba alone to the end.
In a race contested in an entirely different manner, fast from the gun, Ethiopia's Tirunesh Dibaba, a three-time Olympic champion and the women's 5,000m world record holder, won in 2:18:30. Previous year in Rio, Dibaba was third in the 10,000 with the fourth-fastest time in history.
And Dibaba was second at the London Marathon in April in 2:17:56, becoming the third-fastest woman at the distance in only her second try.