The Spaniards, beaten UEFA Cup semi-finalists in 2004 and at the same stage of the Champions League two years later, visit rampant Porto in their semi-final first leg on Thursday while Benfica host Braga in an all-Portuguese affair.
Under the leadership of Manuel Pellegrini, who later went on to manage Real Madrid, Villarreal were beaten 1-0 on aggregate by Valencia in 2004 and by the same score against Arsenal two years later.
However, the Europa League semi-final looks like it could produce goals given Porto's 10-3 demolition of Spartak Moscow in the quarter-finals and Villarreal's 8-2 rout of Twente Enschede.
The match also pits two of European football's most prolific scorers against each other. Porto's Colombian striker Radamel Falcao is the Europa League's leading scorer with 11 goals while Villarreal's Italian forward Giuseppe Rossi is one behind him.
Porto have already been crowned Portuguese champions having won 25 and drawn two of their 27 matches so far, leaving them 19 points clear of Benfica. Andre Villas-Boas's team have been equally formidable in Europe with 12 wins in 14 outings, including all seven away from home.
"I think they're the favourites because they are winning titles," said Villarreal midfielder Bruno Soriano.
"We have to improve our defence to not concede as many goals. If we can do that, we will have taken a big step forward. A 3-2 defeat against Porto would not be a bad result."
However, Porto's form against Spanish teams is uninspiring with only 11 wins in 34 attempts.
The other tie features two sides who dropped into the Europa League after third-place finishes in the group stage of the Champions League.
Braga's European adventure began last July with a qualifying round tie against Celtic.
Since then, they have enjoyed two-leg wins over Sevilla, Liverpool and Dynamo Kiev, as well as Arsenal in their Champions League group.
In complete contrast to free-scoring Porto and Benfica, Braga - who like Villarreal have never won a domestic league title - beat Liverpool 1-0 on aggregate in the round-of-16 and Dynamo on away goals after a 1-1 aggregate draw in the last round.
Benfica, who like Porto have a large South American contingent, badly want to win the Europa League to compensate for a frustrating season in which they have played second fiddle to their bitter rivals from the north.
Having seen Porto clinch the Portuguese league title with a 3-1 win against them in Lisbon, Benfica then blew a two-goal first-leg lead in their Cup semi-final against the same opponents a week ago and went out on away goals.
Nothing would suit them better meeting Porto in the final in Dublin next month.
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