Runs could be hard to come by Thursday as Leake takes the mound opposite Cain, who tries to help the visiting Giants avoid their first four-game sweep against the Reds in 28 seasons.
Leake (7-3, 2.52 ERA) ranks second in the majors with a 1.31 ERA since May 15, going 5-1 over that stretch while allowing one earned run or less in seven of nine outings.
"He's thrown the ball as well as anybody in the league," catcher Devin Mesoraco said.
Leake yielded four runs - one earned - and three hits in seven innings Saturday in a 6-4, 11-inning win at Texas. The three unearned runs came in the third following three Cincinnati errors.
"Leake pitched his heart out," manager Dusty Baker told MLB's official website. "Usually when that happens, when a guy is the recipient of bad things happening behind him, he loses his cool and composure. And he didn't. He's come a long ways. He's really matured right in front of our eyes."
Leake has also baffled the Giants (39-45) during a three-start winning streak in the regular season, posting a 0.77 ERA while striking out 19 and walking two in 23 1-3 innings. Including playoffs, Pablo Sandoval is 8 for 12 with two homers and three doubles against Leake.
Cain (5-4, 4.29), meanwhile, has gone 1-1 with a 1.82 ERA in his last five starts. The three-time All-Star gave up one run and three hits in a season high-tying eight innings Saturday in a 2-1 walkoff loss at Colorado.
"What a great job he did," manager Bruce Bochy said of Cain, who retired the last 20 batters he faced.
Cain is 5-6 with a 3.74 ERA in 12 starts versus Cincinnati (49-36), including the postseason. Jay Bruce is 8 for 10 with a homer and three doubles against him since 2011, while Brandon Phillips is 8 for his last 26 with three homers and two doubles. Joey Votto, though, is 3 for his last 21.
A strong showing from Cain could go a long way for a Giants team that has hit .188 during a 1-9 slide. San Francisco has been outscored 14-3 in losing the first three games of this set, including a 3-2 defeat in 11 innings Wednesday.
San Francisco, which has dropped 10 of 13 regular season matchups to Cincinnati, is in danger of suffering its first four-game sweep in the series since April 18-21, 1985.
Sandoval is mired in a 1-for-29 slump with 11 strikeouts, Hunter Pence is 2 for his last 25 and Buster Posey is hitless in his last nine at-bats.
"We have too many guys scuffling. I don't know why, whether they are pressing or trying too hard," Bochy said. "I wish I had the answer. It seems like we've been saying this for quite a while. We need someone to give us a spark and get a big hit. When you get in a rut like this, you try too hard. We were playing to win one game to get us out of it."
The Reds have won four of five following a 1-6 stretch. Shin-Soo Choo went 2 for 6 on Wednesday, delivering a game-winning two-out single.
"I've been saying that he's one of the best hitters in the game, and I'm sticking with that," third baseman Todd Frazier said of Choo, who's batting .340 in his last 12 home games.
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