Zhirkov is out with a calf problem and Cole is sidelined with a broken ankle, while Paulo Ferreira, who has deputised at left-back before, is not registered for Champions League competition.
Related ArticlesChampions League: liveInter Milan v Chelsea: match previewMourinho: I made Chelsea's starsMilan holds one 'special attraction' for AncelottiAshley Cole flies out to Spanish havenInter Milan v Chelsea: press conference"Definitely it's a problem, we are missing two important players," Ancelotti said.
"Belletti is back, he has been training all week and has been training well. We will definitely find a solution, however, Ashley Cole and Zhirkov are going to be missed."
It is the first time Ancelotti has returned to the San Siro since switching northern Italy for west London last summer.
And the Italian has refuted claims that he believed most Italian supporters would want Chelsea to triumph.
"I never said this, now I work for this club I will try my best for this club," he said.
"Italian fans are interested in this game because it's very interesting for football fans, it's a very important game, two strong teams playing.
"I don't know if Italian fans support Chelsea or not, I am not interested for this, only that Chelsea do the best in this game."
John Obi Mikel lines up against his former mentor tonight aiming for a double over Inter coach Jose Mourinho.
Chelsea met Inter at the Rose Bowl in Pasadena in July and won the game 2-0.
Now the sides meet at the San Siro this evening with Mourinho up against his former club for the first time in a competitive fixture.
Mikel, brought to Chelsea by Mourinho, admits he has a soft spot for his former coach but that will mean nothing when he crosses the white line tonight.
"Mourinho is the man who brought me to Chelsea and this is the first time I will play against him, though we played in a friendly and won 2-0," said Mikel.
"It is a soft spot but we have to do what we did in the friendly and win the game."