Pettitte (5-3) didn't issue a walk and struck out six, placing 59-of-85 pitches for strikes en route to his 250th career victory.
David Robertson notched the final two outs of the eighth and Mariano Rivera struck out three in the ninth for his major league-best 22nd save as the Yankees took their second win in three games against the Mariners.
Joe Saunders (4-6) allowed three runs on seven hits through 6 1/3 innings for Seattle.
Michael Morse drove in the Mariners' only run.
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