The local rivals both go into the game on the back of disappointing 1-0 defeats, with a coronavirus-hit Saint-Etienne losing to Strasbourg, while Lyon's title hopes took a huge blow at home to Metz.
Saint-Etienne will be out for blood after falling to a 2-1 defeat in the most recent Rhone Derby with Lyon, as the two bitter rivals renew hostilities in the pick of the fixtures in Ligue 1 this weekend.
The hosts welcome Lyon to the Stade Geoffroy-Guichard following a run of three draws and two losses from their last five matches, with Claude Puel witnessing his team suffer back-to-back defeats at fellow strugglers Reims and Strasbourg since the turn of the year.
Ryad Boudebouz missed a penalty before Strasbourg's Ludovic Ajorque bagged the winner in last weekend's fixture, but with as many as eight first-team players sidelined after positive COVID-19 tests, Les Verts' chances of victory were always going to be slim.
However, victories have been incredibly hard to come by even for a fully-fit Saint-Etienne squad, as they are only able to boast one win from their last 17 in the top flight to sit 16th in the table - four points clear of the bottom three.
Puel - who himself missed out the loss to Strasbourg due to coronavirus - will hope to be dealing with a less decimated Saint-Etienne squad this weekend as they attempt to defy the odds and prevail at home for the first time since September 12.
Lyon have not exactly covered themselves in glory over the past couple of weeks either, and Rudi Garcia was forced to witness his side suffer their first defeat since September 15 at the weekend.
Les Gones' 16-game unbeaten run came to an end at the hands of Metz, who struck in the dying embers through Aaron Leya Iseka to severely dent Lyon's title hopes at the Groupama Stadium.
Paris Saint-Germain and Lille were both able to take advantage of Lyon's shock defeat, and Garcia's side have now been knocked off their perch to sit third in the table - two points worse off than their title rivals after 20 matches.
As well as last weekend's unforeseen defeat, Lyon only just managed to eke out a win against Lens before playing out a 2-2 draw with Rennes so far this year, and while the Derby du Rhone has produced some feisty encounters down the years, coming up against a Saint-Etienne side bedevilled by injuries and coronavirus could be the perfect tonic for the visitors.
Furthermore, Lyon have taken the spoils in four of their last five away matches in Ligue 1, although four of their last six trips to the Stade Geoffroy-Guichard in the league have ended in defeat.
Saint-Etienne Ligue 1 form: WDDDLL
Lyon Ligue 1 form: DWWWDL
Saint-Etienne were without the likes of Denis Bouanga, Harold Moukoudi, Charles Abi, Zaydou Youssouf, Mathieu Debuchy, Panagiotis Retsos, Romain Hamouma and Yvan Neyou following their coronavirus cluster, with none of those players expected to recover in time for this one.
However, the Verts manager has very few options for change this weekend, but teenage protege Adil Aouchiche could be handed a start in Sunday's derby.
In contrast, Lyon are in terrific shape heading into this showdown, although the influential Lucas Paqueta is suspended for an accumulation of yellow cards.
Islam Slimani made his debut for Les Gones off the bench in last Sunday's defeat, but there is little chance of the 32-year-old starting this one.
Saint-Etienne possible starting lineup:
Moulin; Sissoko, Sow, Kolodziejczak, Trauco; Gourna-Douath, Moueffek; Nordin, Aouchiche, Boudebouz; Krasso
Lyon possible starting lineup:
Lopes; Dubois, Denayer, Marcelo, Cornet; Mendes, Aouar, Guimaraes; Kadewere, Depay, Toko Ekambi
We say: Saint-Etienne 1-3 Lyon
Puel will rally his depleted squad for this all-important derby, and the coronavirus-hit hosts will certainly be aware that Lyon have not been at their free-flowing best in 2021. However, a youthful Verts team will likely be overwhelmed by the quality of Garcia's attacking trio, so we can only envisage Lyon claiming the bragging rights with a comfortable win this weekend.
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