Inter have lost their last three Champions League home matches, including a stunning reverse against Trabzonspor in this season's opener and a 5-2 thrashing by Schalke 04 last season.
In Serie A, Napoli crushed them 3-0 in their own backyard and on Saturday they suffered another miserable evening with a 2-1 defeat to Juventus in the 'Derby of Italy'.
Although Inter top Champions League Group B with six points, it is a precarious lead with Trabzonspor and CSKA Moscow two points behind and bottom-placed Lille four adrift.
Goalkeeper Julio Cesar and fullback Maicon have joined striker Diego Forlan on the injury list in the last week and even refereeing decisions have been unkind with five penalties awarded against them in nine Serie A games.
"Unfortunately we're going through a period when everything's going wrong," said defender Andrea Ranocchia.
"But that's football. However I'm convinced that if we keep on working as we are now to improve our performance, we'll come through this difficult time soon."
Inter, who won 1-0 in Lille two weeks ago, cannot draw any comfort either from their home record against French opposition - they have lost three of the last five fixtures at home to Ligue 1 sides, winning only one.
They slumped to a 1-0 defeat at home to Olympique Marseille in a 2003/04 UEFA Cup quarter-final, the last time they hosted French opponents.
The last Ligue 1 visitors in the Champions League, Olympique Lyon, won 2-1 in 2002/03.
French champions Lille have injury worries, with defenders Aurelien Chedjou (thigh) and Marko Basa (shoulder) very doubtful.
Midfielder Florent Balmont (thigh) is also a major doubt for Wednesday. David Rozenhal and Franck Beria are expected to deputise in central defence.
In the first match, Lille played some nice football but Moussa Sow was isolated up front. Coach Rudi Garcia, however, could field Dimitri Payet alongside the Senegal striker in a 4-4-2 formation.
Lille always have firepower with Belgian prodigy Eden Hazard and former England forward Joe Cole, who has been settling nicely in northern France since joining on loan from Liverpool.
Inter Milan: 12-Luca Castellazzi; 42-Jonathan, 6-Lucio, 23-Andrea Ranocchia, 26-Cristian Chivu; 4-Javier Zanetti, 8-Thiago Motta, 19-Esteban Cambiasso; 10-Wesley Sneijder; 28-Mauro Zarate, 7-Giampaolo Pazzini
Lille: 1-Mickael Landreau; 2-Mathieu Debuchy, 14-David Rozenhal, 18-Franck Beria, 21-Laurent Bonnart; 24-Rio Mavuba, 17-Benoit Pedretti, 10-Eden Hazard, 26-Joe Cole; 7-Dimitri Payet, 8-Moussa Sow
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