Lyon are competing in their 14th European quarter-final, while the Blues are featuring in the last eight of the competition for the fourth time in their history.
Match preview
No side have won more Women's Champions League trophies than Lyon, who collected their eighth European title last season with a 3-1 victory over Barcelona in the final.
Lyon's defence of their European crown began in the worst possible fashion, as they fell to a heavy 5-1 defeat in their home meeting with Arsenal.
However, Sonia Bompastor's side picked up 11 points from their next five group matches to finish in second place and set up a quarter-final tie with Group A winners Chelsea.
A last-eight meeting with the current English champions is a tricky proposition, but Lyon have rarely faltered at this stage of the competition, progressing from 12 of their 13 European quarter-final ties.
Having won all four of their competitive home games in 2023 without conceding, the hosts will be hopeful that they can obtain a first-leg lead on Wednesday.
The closest Chelsea have come to winning this competition was in the 2020-21 season when they made it all the way to the final before being thumped 4-0 by Barcelona.
After being dumped out of the group stage last term, the Blues made no slip-ups this time around, winning five and drawing one of their six group games.
Having cruised through a group that featured the likes of Paris Saint-Germain and Real Madrid, Emma Hayes's side may be quietly confident that they possess the quality to seriously challenge for the European crown this term.
A quarter-final clash with the reigning European Champions represents a significant obstacle, but the Blues can draw inspiration from the fact that they have never been eliminated at this stage of the competition, winning all three of their previous last-eight ties.
Since beginning the month with a League Cup final defeat to Arsenal, the West London side have recorded three straight victories, including a 3-1 win over Reading at the weekend to secure their place in the semi-finals of the FA Cup, ensuring they still have the chance to complete a remarkable treble.
Lyon Women Women's Champions League form:
L
D
W
W
W
D
Lyon Women form (all competitons):
Chelsea Women Women's Champions League form:
W
W
W
D
W
W
Chelsea Women form (all competitions):
Team News
The hosts will go into the first leg without the services of Griedge Mbock, Catarina Macario and Amandine Henry due to injury issues.
Ada Hegerberg is nearing a comeback from a long injury absence, and if passed fit, the Norway international will take up a place on the bench.
After returning from a short spell on the sidelines to feature in Lyon's last two games, Selma Bacha is expected to start on Wednesday.
As for Chelsea, they are still expected to be without the services of Fran Kirby, Pernille Harder and Katerina Svitkova because of injury.
Having missed the last three matches through injury, Erin Cuthbert remains a doubt for the midweek trip to France.
The likes of Ann-Katrin Berger, Kadeisha Buchanan, Melanie Leupolz, Lauren James and Sam Kerr are all expected to return to the lineup after being rested for Sunday's FA Cup win over Reading.
Lyon Women possible starting lineup:
Endler; Carpenter, Gilles, Renard, Bacha; Horan, Egurrola, Dabritz, Marozsan; Casarino, Le Sommer
Chelsea Women possible starting lineup:
Berger; Perisset, Buchanan, Bright, Charles; Leupolz, Ingle; James, Fleming, Reiten; Kerr
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