Rose was born April 14, 1941, in Cincinnati, Ohio, one of four children born to Harry Francis "Pete" and LaVerne Rose. He was a member of the Order of DeMolay as a young boy and was encouraged by his parents to participate in sports. He played baseball and football at Western Hills High School. Although Rose was small for his age, he earned the starting running back position on his freshman football team.

On April 23, 1964, Rose reached first base on an error in the top of the ninth inning of a scoreless game in Colt Stadium and scored on another error. The Colt .45s lost the game in the bottom of the ninth inning and Ken Johnson became the first pitcher to lose a complete game no-hitter. Rose slumped late in the season and was benched; he finished with a .269 average. In order to improve his batting, Rose played in the Venezuelan Winter League with Leones del Caracas team during 1964-1965 season. Rose came back in 1965, leading the league in hits (209) and at-bats (670), and finishing sixth in NL MVP balloting. It was the first of his ten seasons with 200-plus hits, and his .312 batting average was the first of nine consecutive .300 seasons. He hit a career-high 16 home runs in 1966, then switched positions from second base to right field the following year.  In 1968, Rose started the season with a 22-game hitting streak, missed three weeks (including the All-Star Game) with a broken thumb, then had a 19-game hit streak late in the season. He had to finish the season 6-for-9 to beat out Matty Alou and win the first of two close NL batting-title races with a .335 average. He finished second to St. Louis Cardinals pitcher Bob Gibson for the NL MVP award, earning six first place votes.  Rose had his best offensive season in 1969 (the year of the Miracle Mets), when he set a career-high in batting (.348) and tied his career-best 16 homers. As the Reds' leadoff man, he was the team's catalyst, rapping 218 hits, walking 88 times and pacing the league in runs with 120. He hit 33 doubles and 11 triples, drove in 82 runs, slugged .512 (by far the highest mark of his long career), and had a .432 OBP (also a career best). Rose and Roberto Clemente were tied for the batting title going into the final game; Rose bunted for a base hit in his last at-bat of the season to beat out Clemente (.345).

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