The 1921 Centre vs. Harvard football game was a regular-season collegiate American football game played on October 29, 1921, at Harvard Stadium in Boston, Massachusetts. The contest featured the undefeated Centre Praying Colonels, representing Centre College, and the undefeated Harvard Crimson, representing Harvard University. Centre won the game 6–0, despite entering as heavy underdogs, leading to the game being widely viewed as one of the largest upsets in college football history. The game is often referred to by the shorthand C6H0; this originated shortly after the game when a Centre professor remarked that Harvard had been poisoned by this "impossible" chemical formula.

The 1921 Centre Praying Colonels football team represented Centre College of Danville, Kentucky, in the 1921 college football season. Led by coach Charley Moran, the Praying Colonels compiled a 10–1 record, scoring 334 points while allowing 28 points.