Rodriguez's 18th home run of the season came in the second inning against Boston knuckleballer Tim Wakefield. A-Rod took a curtain call after circling the bases.
Next up for the 32-year-old Rodriguez is Mike Schmidt, who finished with 548 homers.
Mantle hit all of his homers for the Yankees in a career that began in 1951 and ended in 1968. Rodriguez has 191 homers since joining the Yankees in 2004.
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