Record winners Sevilla, crosstown rivals Real Betis and Villarreal aim to keep the Spanish flag flying in the Europa League by reaching the knock-out stages on the penultimate matchday Thursday.
Sevilla require only a draw at Standard Liege to reach the last 32, so do Betis against Olympiacos depending on the result of the other game in their group while Villarreal are through if they win in Scotland at Rangers.
Six of the last nine titles in Europe's second-tier event have gone to Spain, with Atletico Madrid and Sevilla winning three each – giving Sevilla a total of five overall as they also lifted the trophy in 2005 and 2006.
Seven clubs have already qualified for the knock-outs, including the English duo of Arsenal and Chelsea and Germany's Eintracht Frankfurt and Bayer Leverkusen.
Sevilla go to Liege with the confidence of Spanish league leaders and joint leaders in Group J on nine points with Russia's Krasnodar. Liege have six and need a victory to stay alive while Turkey's Akhishat are out on zero ahead of their trip to Krasnodar.
Sevilla coach Pablo Machin has remained modest throughout the successful run, saying after the latest league win against Valladolid: "Let's enjoy being top and appreciate what we are achieving."
Villarreal meanwhile langiush in 14th place in La Liga ahead of their Rangers date but hope that a weekend 2-1 over Betis to end a run of five games without success is a sign of better times to come.
“We hope the win against Betis is a turning point for our season. The important thing now is to keep the momentum going with a win in Glasgow," midfielder Santi Cazerlo said.
Villarreal can not afford to drop points in tight group G where all four teams are still alive. They top the group on six points but Rangers and Spartak Moscow have five each and Rapid Vienna, who go to to Moscow in the other game, four.
Betis are also top of their group F on eight points, with AC Milan – who host eliminated Dudelange in the other game – and Olympiacos on seven each.
They have scored stunning away victories at Barcelona in La Liga and at AC Milan in the Europa League but now want to finally win at home again for the first time in all events since a 3-0 over Dudelange in early October.
But coach Quique Setien said: "We are a team in the making, we still lack some things. I have a lot of confidence in this team, they are growing, we have a good performance rate."
Milan will be hoping for a draw in Seville while they are big favourites against Dudelange, with coach Gennaro Gattuso planning a two-man strike force of Gonzalo Higuain and Patrick Cutrone.
"Gonzalo will play and I hope that Patrick recovers as we will try to play with two hitters bacause it is a game we must win at all costs," gattuso said.
Things are a complicated in Group I where all four teams are still alive. Leaders Genk (seven) are at Malmo (five) who are joint second with Sarpsborg who host Besiktas (four).
Other clubs who can clinch their place in the last 16 include former champions Zenit St Petersburg, last season's semi-finalists Salzburg and Dynamo Kiev.
Topping a group is also important because winners will avoid the four best teams dropping down from the Champions League in the last 32 draw, and have the return leg of that stage at home.
No wonder Arsenal manager Unai Emery, who guided Sevilla to their title treble 2014-2016, is unlikely to bring out reserves only at Ukraine's Vorskla even though the Gunners then face Tottenham in the league on Sunday.
"For us the Europa League is very important. We want to finish first in the group," Emery said.