Second-half strikes from Jonathan David and Edon Zhegrova earned Lille a 2-0 win at the Stade du Hainaut in Valenciennes last week, taking them within touching distance of a place in the UEFA Champions League group phase.
It isn't an impossible job for Slavia who have lost a European first-leg tie by two goals or more seven times, and overturned that deficit on three occasions.
However, Lille have won seven of the 10 ties in which they won the home leg, most recently against Fenerbache in this season's third qualifying round.
Slavia Prague v Lille is available to watch live on TNT Sports 1.
Slavia Prague v Lille will kick off at 20:00 BST on Wednesday 28th August at the Eden Arena in Prague.
These sides have met three times in European football, the first two occasions in the group stage of the 2009/10 UEFA Europa League when the French side won 3-1 at home and 5-1 away.
They then met in last week's first leg of this UEFA Champions League play-off round tie, and again it was Lille who prevailed, this time 2-0.
Lille, unbeaten this season, go into the game on the back of three straight 2-0 victories.
Slavia had won six in a row before losing at the Stade du Hainaut.
Slavia Prague wins | 0 |
Draws | 0 |
Lille wins | 3 |
* H2H stats refer to all competitions
Slavia are without Czech keeper Jindrich Stanek and fellow international defender Tomas Vlcek.
Right wing-back Lukas Masopust limped out of the first leg with a hamstring injury.
Right-sided centre-back Aissa Mandi is suspended which means Thomas Meunier should play there.
Centre-back Samuel Umtiti and midfielders Nabil Bentaleb and Angel Gomes remain out for Bruno Genesio's side.