Jürgen Klopp was denied a return to the elite level of European competition by Sevilla back in May 2016, when the Andalusian outfit beat his side in the Europa League final.
Liverpool have the opportunity to show Sevilla how far they have come since that night, and much of the attention will be on playmaker Philippe Coutinho.
The Brazilian is available to Klopp and could make his first start since submitting a transfer request in an attempt to force through a move to Barcelona last month.
Will Coutinho start and, if he does, who could Klopp select to line up alongside him?
As Klopp confirmed on Monday, Loris Karius will make his Champions League debut and start in goal for Liverpool, with Simon Mignolet dropping out of the side.
The 24-year-old’s experience of European competition amounts to just two Europa League games with former club Mainz, but Klopp believes Karius deserves the chance to play after training well.
Dejan Lovren missed Saturday’s defeat at the Etihad after “feeling the intensity” of the September international break, but the Croatian is expected to take up a position alongside Joel Matip once again on Wednesday night.
Jordan Henderson was poor against City but as captain, will be entrusted with a place in front of the back four on Wednesday. Klopp, meanwhile, will hope that Emre Can can re-create his pre-international break form.
The front three does not need changing, provided that Mohamed Salah recovers from the slight illness that kept him out of Tuesday’s training session. The Egyptian, who has been worryingly wasteful in front of goal, should start on the right with Sadio Mané on the left and Roberto Firmino through the middle.
Both full-back positions remain up in the air, with Trent Alexander-Arnold enduring a difficult afternoon at the Etihad. With long-term absentee Nathaniel Clyne omitted from the 22-man Champions League squad, Joe Gomez could be preferred at right-back.
On the other flank, Alberto Moreno has probably done enough to retain his position and start, despite memories of his calamitous display against his former club in the 2016 Europa League final. Andrew Robertson is his competition for the left-back berth, but the Scot is more likely to feature when Burnley visit Anfield this weekend.
Georginio Wijnaldum has had a mixed start to the season but is yet to begin a matchday on the substitutes’ bench. Now might be time for a rest. James Milner and Alex Oxlade-Chamberlain are both waiting in the wings but there is also, of course, Philippe Coutinho. Is now the right time to reintegrate him? Should he play from the off or should there be a sheepish second-half introduction as a substitute, a la Alexis Sanchez at the weekend? We must wait and see.
The Independent’s predicted Liverpool XI vs Sevilla: Karius; Gomez, Matip, Lovren, Moreno; Henderson, Can, Coutinho; Salah, Firmino, Mané.