Milan seek revenge against Chelsea with Theo Hernandez back and Brahim Diaz in his new wider role, while Jorginho and Kalidou Koulibaly start at San Siro.
It kicks off at the Stadio Giuseppe Meazza at 20.00 UK time (19.00 GMT).
The Rossoneri were beaten 3-0 at Stamford Bridge last week in the middle of an injury crisis, but recovered in Serie A to defeat Juventus 2-0 on Saturday.
Theo Hernandez was available again after missing the London trip and the other change was Stefano Pioli shelving the 4-2-3-1 formation in favour of a 4-3-3.
This allows Rafael Leao and Brahim Diaz to take even wider roles supporting Olivier Giroud, while Rade Krunic bolsters the midfield rather than Tommaso Pobega.
They are still missing Mike Maignan, Davide Calabria, Simon Kjaer, Alessandro Florenzi, Alexis Saelemaekers, Zlatan Ibrahimovic and now also Charles De Ketelaere.
Also unavailable in Europe are Yacine Adli, Malick Thiaw, Aster Vranckx and Tiemoue Bakayoko.
Rather than Sergino Dest, Milan shift Pierre Kalulu to right-back and give Matteo Gabbia a chance in central defence.
Wesley Fofana scored in London, but he is out injured along with N’Golo Kante and Hakim Ziyech.
Former Napoli stars Koulibaly and Jorginho start, while Thiago Silva and Pierre-Emerick Aubameyang spent time at Milan.
Milan: Tatarusanu; Kalulu, Gabbia, Tomori, Theo Hernandez; Krunic, Bennacer, Tonali; Brahim Diaz, Giroud, Leao
Chelsea: Kepa; Chalobah, Thiago Silva, Koulibaly; James, Jorginho, Kovacic, Chilwell; Sterling, Mount; Aubameyang