The right-hander has completely shut down Chicago since being acquired by the Royals last summer, and he'll look to add to the visiting White Sox's woes in the opener of a three-game series Friday night.
Guthrie came to Kansas City in a deal for left-hander Jonathan Sanchez on July 19, and he's gone 3-0 with a 0.40 ERA in six starts against the White Sox. The Royals have won all six games, and Guthrie has allowed one run over 15 innings in winning both outings this season.
He pitched a four-hitter in his first career shutout in the last matchup May 4, walking one in a 2-0 victory in Kansas City.
"He's been tough on us," White Sox manager Robin Ventura said. "First, because he's good. ... He seems to pick it up when we're facing him. ... You have to pick your poison, you go after him early and then you pop it up. He's tough."
Guthrie beat Baltimore in his next start May 9 to increase his club record to 18 consecutive outings without a defeat and improve to 5-0 with a 2.28 ERA on the season. However, he's struggled since, going 2-4 with a 5.24 ERA in his past seven starts.
Guthrie (7-4, 3.72 ERA) gave up three home runs in a 5-3 loss at Tampa Bay on Saturday and leads the majors with 19 allowed.
"I'd like someone to pass me," Guthrie told the Royals' official website. "It's hard for them to pass me, I'm going real fast."
Guthrie has not allowed a home run in 44 2-3 innings against the White Sox (29-41) since joining the Royals (34-36).
Paul Konerko and Adam Dunn hit back-to-back homers in Minnesota on Thursday, but it wasn't enough as the White Sox lost 8-4.
Chicago has dropped three straight, seven of eight and 17 of 22 games. The White Sox are 12 games under .500 for the first time since the last day of the 2007 season.
"We truly feel like we're way too good to be playing like this," pitcher John Danks said. "We feel we're just as talented as any team in the league."
The Royals are 12-6 in June but have lost two in a row, falling 6-3 in Cleveland on Wednesday night.
"It's tough," left fielder Alex Gordon said. "... We would have loved to turn these last two games around. We could have. We had our opportunities and just didn't do it."
Kansas City will be facing Hector Santiago (2-5, 3.30), who has been filling in for the injured Jake Peavy. The left-hander has been in and out of the rotation this season, going 2-3 with a 3.00 ERA in seven starts.
He lost 5-4 in Houston on Sunday after giving up three runs in the second inning.
"Like I said earlier in the year, it's always one inning," Santiago told the White Sox's official website. "First, second inning I get in trouble and then I settled in, but I have to get to the point where I get through the first two innings. Get through those and it seems like we're good from there."
Santiago has not allowed a run while striking out 13 in 11 1-3 career innings against the Royals. He's made one start, allowing three hits in four innings opposite Guthrie on Sept. 9 when the Royals won 2-1 in 10 innings in Chicago.