As the dominant force in European women's football for the past few seasons, Lyon are gunning for a fifth successive Champions League title, but a two-city, straight knockout format in Spain could offer other clubs hope of a new name on the trophy.
The traditional home-and-away ties have been replaced by an eight-team mini tournament that will be played in San Sebastian and Bilbao because of complications caused by the coronavirus pandemic.
Mirroring the men's competition in Lisbon, all games will be staged behind closed doors in a country which counts around 350,000 COVID-19 infections, the highest amount in Western Europe.
Lyon were crowned French champions for the 14th time in a row when the season was declared over in May as a result of the virus outbreak. They claimed a record-extending ninth French Cup earlier this month after beating Paris Saint-Germain on penalties.
Despite just two competitive outings since February, Lyon coach Jean-Luc Vasseur is confident his side can defend their European crown.
"We saw that all the players were ready to go to Spain," Vasseur said after a recent 3-0 friendly win over Juventus.
"I think with the group I have, we're not afraid of the unknown. We hope this situation with virus passes quickly. We all want to return to a normal life."
Lyon face Bayern Munich in the quarter-finals on Saturday, 72 hours after the two clubs meet in the men's semi-finals in Portugal.
However, Lyon are expected to be without Norwegian star Ada Hegerberg who is only six months removed from surgery on ruptured knee ligaments. The 2018 Ballon d'Or winner is the Champions League's all-time leading scorer with 53 goals.
Dutch international Shanice van de Sanden knows Lyon, who coasted through the previous two rounds winning 16-0 and 11-0 respectively, cannot afford a false step in this unique format.
"Usually, if you don't play well in the first game, you have a chance to put it right, but now if we lose we're out of the Champions League," Van de Sanden told FIFA.com.
"It's the same with the Euros or the World Cup –- anything can happen. It's about the team that gets into the flow."
- Advantage Germany? -
Twice former winners Wolfsburg take on Glasgow City on Friday, at the same time as the all-Spanish clash between last year's runners-up Barcelona and first-time quarter-finalists Atletico Madrid.
Wolfsburg, champions in 2013 and 2014, appear Lyon's most likely challengers for the trophy, and have the benefit of playing regular competitive matches in recent months, as the German league resumed and finished its season.
In contrast, women's leagues in Spain and England were cut short, while football in France was cancelled after the government intervened. Scotland's season was called off after just one round of matches.
"Obviously we're expected to overcome the hurdle of Glasgow," said head coach Stephan Lerch, who can call upon the Frauen Bundesliga's 27-goal top scorer and Denmark captain Pernille Harder.
Arsenal, who won the 2007 edition, play two-time runners-up PSG in Saturday's other quarter-final.
Clubs will be allowed to register six new players for the 'Final Eight', as several were unable to extend existing contracts due to financial constraints amid the pandemic. Only three of those are allowed to have played for one of the other quarter-finalists.
Players and staff must also undergo virus testing before departing for Spain and again on the eve of each match.
Atletico's preparations suffered a considerable setback when the club was forced to suspend training last week following five positive COVID-19 tests among the squad and coaching staff.
The northern Basque region, which incorporates the two tournament venues, on Monday declared a health emergency because of the risk of a "tsunami" of new infections as Spain reimposed measures to curb one of the fastest virus growth rates on the continent.