Galen Rupp of Portland, Oregon, crossed the finished line at 2:09:20, while Kenyan Abel Kirui came in second, 28 seconds behind Rupp. Another Kenyan, Bernard Kipyego, was third.
The last American to win the men's race was Khalid Khannouchi in 2002.The women's race was won by Ethiopian Tirunesh Dibaba in 2 hours 18 minutes and 31 seconds. Brigid Kosgei of Kenya came second and American Jordan Hasay was third.
More than 40,000 runners started the 40th annual Chicago Marathon and more than a million spectators lined the route.
McFadden, an Atholton graduate who has dominated the Paralympic marathon scene in recent years, had surgery in the spring to alleviate blood clots. She competed in the Boston Marathon in April just weeks after the surgery, finishing fourth.
Prior to Boston, the 28-year-old McFadden won the four major marathons — Boston, Chicago, New York and London — for four straight years and earned six medals at the Rio Paralympics in 2016.
"Wow what an incredible day to be back with my fast and fierce competitors … we were able to get a new course record!!," McFadden tweeted after Sunday's race. "Thank you to everyone for the wonderful support. … It's incredible to be back since the injury back in February."