During his lengthy career, Millwood has posted an 0-3 record with a 4.85 ERA in six career starts on the South Side.
He'll hope to change that on Sunday when the White Sox go for a three-game series sweep.
A bit unlucky this season, Millwood is 4-10 with a 4.29 ERA and is just 1-6 with a 4.68 ERA over his last 15 starts.
He picked up a no-decision in his last outing on Monday against the Indians, allowing three runs on five hits in six innings during a 5-3 Mariners win.
"I was locating my fastball pretty well. I threw some pretty good offspeed pitches," Millwood said after the contest. "Nothing was outstanding, but it was enough to at least give us a chance. Nothing was great, but everything was serviceable.
Meanwhile, Gavin Floyd will be on the hill for the White Sox, ready to rebound after a rough start against the Yankees on Monday.
After giving up three runs on five hits in just 2 1/3 innings of work, Floyd was visibly upset with his performance, throwing and kicking things in the dugout after being removed.
"You want to go out there and give your team your best effort, and I felt like I was below where I wanted to be," Floyd said after a 9-6 White Sox win. "It's frustrating, but our team battled today and ended up winning today, so that was a good part."
Mariners: Saunders and Thames get day off
Center fielder Michael Saunders and right fielder Eric Thames were out of the starting lineup for Saturday's game against the White Sox after colliding on the final play of Friday's 9-8 loss.
Saunders injured his groin muscle slightly as the two crashed together and received treatment prior to Saturday game at U.S. Cellular Field.
"Thames is OK. Saunders has a little bit of groin," manager Eric Wedge said. "When they hit out there, he kind of stuck and turned in a way that was kind of funky. He'll be a game-time decision in regard to his availability. Eric is good to go, but they've got a lefty in there tonight so we've got our other guys in there."
Thames entered the Mariners' 5-4 loss in the eighth inning and singled in his lone at-bat.White Sox: Pierzynski, Ventura ejected in Saturday's game
White Sox starting catcher A.J. Pierzynski and manager Robin Ventura were ejected in the third inning of Saturday's contest against the Mariners for arguing balls and strikes with home-plate umpire Lance Barrett.
Pierzynski took exception to a first-pitch ball called on a fastball from White Sox starter Jose Quintana to Justin Smoak with one out in the inning. Barrett then tossed Pierzynski, who was kept away from Barrett by Ventura. As Ventura continued to argue, he was also ejected by Barrett.
It marked the third ejection for Ventura, with the last one coming July 8 against Toronto. Pierzynski was ejected for the sixth time in his career, with the last one coming April 20, 2011, against Tampa Bay.
Former Mariners reliever David Pauley, now pitching for Triple-A Tacoma, has been suspended for 50 games without pay following a second violation for a drug of abuse, according to the Commissioner's Office.
Dayan Viciedo was scratched from the White Sox starting lineup on Saturday with soreness in his right shoulder. Jordan Danks took over in left field for Viciedo, who is hitting .254 with 19 homers and 57 RBIs, but has three homers and seven RBIs in his last 14 games.