| Centre vs. Harvard, 1921 | |||||||||||||||||||
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 Cover of the official game program | |||||||||||||||||||
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| Date | October 29, 1921 | ||||||||||||||||||
| Season | 1921 | ||||||||||||||||||
| Stadium | Harvard Stadium | ||||||||||||||||||
| Location | Boston, Massachusetts, U.S. | ||||||||||||||||||
| Referee | R. W. Maxwell | ||||||||||||||||||
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, and the game is widely viewed as one of the largest upsets in college football history. The game is often referred to by the shorthand C6H0, after a Centre professor's remark that Harvard had been poisoned by this "impossible" chemical formula.
The teams had met for the first time in the previous year. Centre, led by Charley Moran, shocked many by taking a tie into halftime but ultimately Bob Fisher's Harvard squad took control in the second half and won the game. Centre played well enough to warrant a rematch the following year, and the Colonels, led by quarterback Bo McMillin and halfback Norris Armstrong, again found themselves tied with the Crimson at halftime. Less than two minutes into the game's third quarter, McMillin rushed for a touchdown, the only score of the game, giving the visitors a 6–0 lead. The conversion failed but the Centre defense held for the remainder of the game. Harvard threatened and even reached the Centre 3-yard line at one point but were unable to score. Regaining possession with several minutes remaining in the game, the Praying Colonels ran out the clock to secure a six-point victory and maintain their perfect record.
Once word of the victory arrived in Danville, Kentucky, Centre students began writing the "impossible formula" around campus. When team members returned two days after the game, they were received as heroes and were paraded down Main Street by a party that included Governor Edwin P. Morrow. Harvard lost its game with Princeton the following week and finished the season with a 7–2–1 record, while Centre finished the regular season with four wins before defeating Arizona in the 1921 San Diego East-West Christmas Classic. Centre's lone defeat came to Texas A&M in the 1922 Dixie Classic on January 2, leaving them with a 10–1 record.