Santana takes the mound for Kansas City against the visiting White Sox on Tuesday night in the opener of a three-game series.
The Royals (64-59) are all but out of the AL Central race after losing three of five to Detroit to fall 8 1/2 games behind the Tigers. Saturday and Sunday's losses were blown opportunities after Kansas City swept Friday's doubleheader.
"We had a chance to win the series," manager Ned Yost said after Sunday's 6-3 setback.
A wild-card spot is still attainable for the Royals, who haven't made the playoffs since 1985.
Santana (8-6, 3.19 ERA) has been one of the AL's best this year, posting a career-low ERA in his first season with Kansas City. He's been especially good since giving up season highs of eight runs and 10 hits over five-plus innings against the New York Yankees on July 11, going 3-0 with a 2.61 ERA in six starts.
The right-hander was in line for another win Wednesday, allowing one run in six innings, but a seventh-inning error contributed to a 5-2 defeat to Miami. It was just the second time in nine games Kansas City lost one of Santana's starts.
The White Sox (49-74) have been essentially out of postseason contention for weeks with one of baseball's worst records, but have won three in a row and nine of 14 since dropping 10 consecutive games.
Alexei Ramirez was a triple shy of a cycle and drove in three runs in a 5-2 win at Minnesota on Sunday. He's batting .379 while collecting a hit in 14 of his last 15 games, and has driven in 11 runs in 11 contests since being slid down to the No. 3 spot in the lineup.
"I still basically do the same thing," said Ramirez, whose .289 average is his best since he hit .290 as a rookie in 2008. "If I have a runner in scoring position, I'm doing whatever I can to bring him home. For me, it's a special place to hit."
Ramirez should feel comfortable versus Santana, whom he's 8 for 24 against.
Kansas City could use some better production after plating 16 runs and going 8 for 61 (.131) with runners in scoring position in losing five of seven. Billy Butler and Alcides Escobar have combined to go 1 for 18 in those situations.
Butler and Alex Gordon are a combined 9 for 52 with 12 strikeouts off scheduled starter John Danks, while Eric Hosmer is 4 for 8.
Danks (2-10, 4.54) is trying to end an eight-start winless streak in which he's 0-5 with a 4.70 ERA. The left-hander gave up six runs - four earned - and nine hits over 7 1-3 innings of a 6-4 loss to Detroit on Wednesday.
Danks is 4-0 with a 2.27 ERA in his last six starts against the Royals, but hasn't faced them since Sept. 24, 2011.
Santana, whose only appearance against the White Sox this season came in his 2013 debut, is 5-5 in 16 career games versus Chicago with a 4.06 ERA.
The Royals swept a three-game series at Chicago at the end of July, and have won seven of 12 meetings this year.
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