Nix, whose two other starts came in left field, has not played shortstop in a regular-season game since 2010, when he was a member of the Chicago White Sox. His last start at the position came in 2009, but the Yankees played him there in Spring Training this year.
Nix entered Saturday with no hits and no walks in seven plate appearances this season, but he quickly changed that by hitting a two-run home run to cap a four-run second inning that saw the Yankees take a 4-0 lead over the Mariners.
"I have to pick my spots to rest Derek," manager Joe Girardi said. "This is a guy who's played in every game. People were talking about 140, 145 games. We've been fortunate to play him in every game this year, and he's been productive."
Nix became the Yankees' choice after the team demoted Eduardo Nunez following a two-error performance in Thursday's win over the Rays. Nunez will play shortstop and second base in the Minor Leagues as the team looks for other options to rest Jeter and Alex Rodriguez during a stretch of 16 games without an off-day.
"What I worry about is that when they are fatigued, they're going to pull something," Girardi said. "That's my concern. I've been more proactive with Alex than I have been with Derek. I'm just trying to be proactive. We're in a stretch of 16 games. I'm going to have to pick a couple of spots for each of them."
Jeter has started every Yankees game this season, and Rodriguez has started 32 of 33 and appeared in every game. In 2011, he played in only 99 games after missing time due to knee surgery.