In a quirk of the fixture list the two sides also met at the weekend in La Liga with Athletic triumphing 2-0 in Bilbao, so this will be the third meeting between the sides in seven days.
Sevilla boast an extremely strong record in their own stadium, where they have lost just once in their last 20 matches, and their run of ten consecutive home wins came to an end with a 1-1 draw against Atletico Madrid last time out.
Watch and bet live on Sevilla vs Athletic Club
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Athletic striker Aritz Aduriz had to come off just before half-time in the first leg and missed the league game on Sunday. He should though be available for selection for Wednesday's match.
Meanwhile, Nolito scored in the first leg for Sevilla but has been ruled out for three months with a calf injury.
Athletic made a number of changes to the starting eleven in the first leg and despite boasting a proud history in this competition, their priorities lie elsewhere.
Avoiding a first ever relegation from the top flight is a far more pressing matter for the Basques, who are just three points above safety and have a massive La Liga game at fellow strugglers Villarreal this weekend.
Sevilla's home form is excellent while Athletic have really struggled on the road over the last couple of years, winning just four of their last 27 away matches in the Primera Division.
Tips and predictions
Everything points to a victory for the hosts and the price of 7/10 (1.70) for them to win their twelfth home game in all competitions this term should be of interest.
Seven of Sevilla's 11 victories at the Sanchez Pizjuan this season have come without conceding and a repeat is offered at 21/10 (3.10).
Odds correct at time of writing. Please gamble responsibly.