Betis currently occupy one of the six European spots on offer, whilst Valencia have some work to do if they wish to climb up the La Liga table.
There has been little to separate both Betis and Valencia over the past few seasons, with neither side able to register back-to-back victories in any of the previous eight meetings.
Valencia were the last team to notch consecutive wins in this fixture, triumphing during both clashes of the 2017-18 campaign, but that remains the only occasion it has happened since November 2008.
However, it is in fact Betis who have the current upper hand in this tie, having gone unbeaten in the previous two meetings, and they will secure their longest streak without losing against Valencia since 2016, should they avoid defeat on Wednesday.
It is likely Manuel Pellegrini will enter the match confident of his side earning a result, as they have picked up from where they left off last season and started the campaign in fine form.
Losing just two of their nine La Liga matches so far, Betis are sitting pretty in fifth and could make the leap into the Champions League spots, should other results go their way.
A lengthy 15 years have passed since the Andalusian club last competed in Europe's premier competition, with a return to the Champions League not an unthinkable target for a well-drilled Betis side.
Pellegrini has vast experience taking mid-table Spanish sides deep into the Champions League, having reached the semi-finals during both his Villarreal and Malaga reigns.
Whilst that remains the dream, the former Manchester City boss will have some of his attention fixed on Betis' current European campaign, where Los Verdiblancos are well positioned to qualify for their second Europa League knockouts in four seasons.
Second in the table after three matches and yet to be beaten, Betis could secure qualification when they travel to face Bayer Leverkusen in a week's time.
First however is the small task of Valencia, who may have missed the boat for Champions League qualification, but could still compete for a spot in the other two continental competitions.
Floating around mid-table, Jose Bordalas's side have failed to build on their own positive start to the campaign and will travel South in the midst of a turbulent run of form.
Three wins from their first four were followed up by a six-game winless streak, including a trio of defeats in five matches.
Bouncing back will not be easy against an in-form Betis side, and Valencia will be keen to pick up three points in an attempt to get their season back on track.
Finding a way to stop Willian Jose could prove tricky for Valencia, as the forward has four goals for Betis since joining on loan from league leaders Real Sociedad, and he will likely lead the line just in front of Nabil Fekir.
Fekir has one assist so far this season, yet it is Guido Rodriguez who leads the creativity charts for Betis, setting up two goals up to now.
Part of Betis' strong form has in part been down to their good luck with injuries and they look set for another game without many absentees, as Youssouf Sabaly is likely the only player to be unavailable for Pellegrini.
Similarly, Valencia have a clean bill of health ahead of their trip to Seville, leaving few excuses for Bordalas's men to compete against Betis.
It is likely the attacking responsibilities will fall onto the shoulders of Carlos Soler, whose three goals this season remain the most for any Valencia player so far.
Denis Cheryshev provided a boost for the Valencia attack after returning from injury last time out, and the one-time Champions League winner with Real Madrid could feature alongside Soler.
Real Betis possible starting lineup:
Bravo; Bellerin, Bartra, Gonzalez, Moreno; Rodriguez, Canales; Rodri, Fekir, Juanmi; Willian Jose
Valencia possible starting lineup:
Cillessen; Foulquier, Gabriel, Diakhaby, Gaya; Helder Costa, Wass, Racic, Duro; Gomez, Guedes
We say: Real Betis 2-1 Valencia
Betis are in the midst of some of their best form in decades and a return to the Champions League is not yet out of the question.
It is games against the teams just below them that will determine their fate and with the support of the Benito Villamarin behind them, another victory could be on the cards.
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