Iberian hopes of a Europa League bonanza could be boosted on Thursday when both Manchester giants United and City face a battle to stay in Europe.
After crashing out of the Champions League, United were labelled possible winners of Europe's second-tier club competition -- an assumption that was kept in check last week when Athletic Bilbao romped to an impressive 3-2 win at Old Trafford.
Conceding three goals at the Theatre of Dreams has now given Sir Alex Ferguson the nightmare scenario of a possible exit at Bilbao's imposing San Mames stadium.
The Cathedral, built in 1913, is the oldest stadium in the Spanish league and is well known for the special, intimate atmosphere that Athletic fans will be hoping plays a part as they bid for a first quarter-final appearance since 1977.
However, the hosts have a concern over Spain international striker Fernando Llorente, who cancelled out Wayne Rooney's opener last week at Old Trafford and also scored at the weekend in a 2-1 away defeat by Osasuna.
He is suffering from a sore left thigh, and could face a last-minute fitness check from Argentine coach Marcelo Bielsa.
After admitting that Bilbao "were the better team" in the first leg, Ferguson conceded that the demands of challenging on two fronts could ultimately undo his team's European ambitions.
"The question is can we win the match? I think we can win the match over there," he said.
"Maybe we are finding it difficult to marry the two competitions together, Thursday-Sunday. It's more difficult than the normal Champions League. But I think we can win the game okay."
City, meanwhile, returned from Lisbon licking their wounds after suffering a 1-0 defeat by Sporting.
Having gone on to concede top spot to United after a shock 1-0 Premier League defeat at Swansea City, Thursday's game represents a turning point that City must negotiate smartly if they are to also keep momentum for their domestic challenge.
Defender Micah Richards admits City have lost some of their shine, but says they are determined to put their recent problems behind them.
"Teams are defending better against us," he said.
"At the start of the season we were scoring, four, five or six goals a game, but in the last two games we have not hit the net and it is something we want to look at and improve on in the next couple of games."
Elsewhere, Atletico Madrid travel to Besiktas hoping to avoid an upset as they look to repeat their feat of two years ago when Fulham fell 2-1 to the Spaniards in the Hamburg final.
Valencia, third in La Liga, face an arguably stiffer challenge when they travel to Eindhoven in the Netherlands.
The Spaniards were enjoying a 4-0 home win against PSV last week, only to take their foot off the pedal and allow the Dutch to score two late goals.
That result was nonetheless one of three contributory factors behind the sacking of PSV coach Fred Rutten, who lost his job on Monday -- the other two being league defeats against FC Twente (2-6) and NAC Breda (3-1).
The hosts now go into the match under former assistant coach Phillip Cocu, the ex-Netherlands international midfielder.
Last season's Champions League semi-finalists Schalke 04 hope Spanish great Raul has his scoring boots on as they host Twente in the hope of overturning a 1-0 first-leg deficit against Steve McClaren's side.
Fellow Bundesliga representatives Hannover will savour home advantage as they host Standard Liege a week after a 2-2 draw in Belgium.
The only Italian side left in the competition, Udinese, have it all to do at home against the third Dutch side, AZ Alkmaar, who have a 2-0 first-leg cushion.
Olympiakos, meanwhile, boast a 1-0 advantage against Ukrainian visitors Metalist Kharkiv.