The struggling Indians have been awful against left-handers all year and Pettitte has been excellent at home as he looks to help the Yankees post their fifth straight victory Wednesday.
New York (45-28) is in position for its first three-game home sweep of Cleveland (37-36) since April 17-19, 2007. Hiroki Kuroda yielded one run over seven innings in Monday's 7-1 rout and Phil Hughes threw eight scoreless frames in Tuesday's 6-4 victory.
The Indians entered this series with a major league-leading 32-19 mark when they face right-handers, but their 5-15 record against left-handers is the worst in the AL.
Pettitte (3-3, 3.29 ERA) presents a monumental challenge since he seems to be tailor-made for the new Yankee Stadium, where he is 3-0 with a 1.27 ERA with 35 strikeouts over 28 1-3 innings in his last four outings.
He dropped his last start Friday on the road to the Mets, giving up five runs over six innings in a 6-4 defeat.
Pettitte's eight career regular-season wins over Cleveland represent his lowest total against any AL team.
His battery mate Wednesday is expected to be Russell Martin, who has missed the last three games with back stiffness. Martin took batting practice Tuesday.
"It's not going to be 100 percent, I don't think," Martin told the Yankees' official website. "But as long as I take swings and it doesn't feel like it's getting worse, then I'll be satisfied with that."
These teams are among the majors' leaders in walks with 261 for New York and 259 for Cleveland.
The Yankees figure to be better poised to take advantage of their plate discipline Wednesday since they will face Ubaldo Jimenez (7-5, 4.59), who has baseball's worst walks per nine-inning ratio at 5.36.
Jimenez overcame four free passes as he allowed four hits over 6 2-3 innings Friday for a 2-0 victory at Houston.
The right-hander won his lone career start against the Yankees on the road last June 24 as he yielded two runs over seven innings in a 4-2 victory.
Martin has a .457 on-base percentage against Jimenez, going 9 for 28 with seven walks.
Manager Joe Girardi used Curtis Granderson as his designated hitter Monday and Raul Ibanez on Tuesday while hinting that Mark Teixeira could get a day off from the field Wednesday.
"We're seeing a lot of right-handers in this 10-day stretch that we're (in) so I'm trying to give Raul a day, I may possibly give Tex a day tomorrow where he gets a DH day," Girardi said.
The Indians are trying to avoid their first five-game slide since June 2-6, 2011. They scored one run in each of the first three defeats before avoiding a shutout Tuesday with a four-run ninth.
Cleveland's 12-19 record in day games is the AL's second-worst. New York is 13-8, playing the majors' fewest such contests.