Second-seeded Michigan State was shocked by No. 15 seed Middle Tennessee State 90-81.
The Spartans played from behind all day and trailed 41-35 at halftime to the No. 15 seed Conference USA champion at Scottrade Center in St. Louis Missouri.
Reggie Upshaw scored 21 points to lead the balanced Blue Raiders (25-9), who shut down player of the year candidate Denzel Valentine. Middle Tennessee never trailed the Spartans (29-6) in one of the biggest upsets since the tournament began seeding teams in 1985.
It is the eighth time in history that a 15-seed has upset the No. 2 seed, and first since Florida Gulf Coast beat Georgetown in 2013. The Eagles went on to reach the Sweet 16.
"We just got beat," Coach Tom Izzo said. "But I want everybody to know this team had a chance to win a national championship. I don't feel one bit different.
"I'll be honest with you, in my wildest dreams I didn't think they'd hit some of the shots they hit. We didn't guard them good, but man, they made some shots."
Middle Tennessee State advances to play Syracuse in the second round Sunday.