Both sides have already met once this season, with As Aguias cruising to a 4-1 victory in their Primeira Liga clash on September 14 thanks to goals from Kerem Akturkoglu, Florentino Luis, Antonio Silva and Angel Di Maria.
Match preview
Benfica turned in an attacking show of class on Sunday as they steamrolled Rio Ave 5-0 when the two teams squared off at the Estadio da Luz to remain within eight points of first-placed Sporting Lisbon in the Primeira Liga table.
Artukoglu netted a sensational first-half hat-trick to put the hosts in a commanding lead before substitutes Andreas Schjelderup and Zeki Amdoubi added to the scoreline later on to cap off a dominant team display.
Prior to that, Benfica's 100% record in the Champions League came to an end on October 23, when they were beaten 3-1 by Feyenoord on home turf courtesy of a brace from Antoni Milambo and Ayase Ueda's first-half strike.
Since suffering a 2-0 loss against Famalicao in their Primeira Liga opener on August 11, Bruno Lage's men have gone unbeaten in each of their subsequent seven league matches, claiming six wins and one draw to collect 19 points from a possible 27.
Benfica now turn their focus to the Taca da Liga, where they will be looking improve their disappointing performance from last term, when they lost on penalties to Estoril Praia in the semi-finals following a 1-1 stalemate in normal time.
Santa Clara, on the other hand, returned to winning ways last Sunday as they held on to see out a 2-1 victory over Gil Vicente when the two teams met at the Estadio de Sao Miguel.
Sidney Lima and Diego Calila scored on either side of Santi Garcia's 28th-minute equaliser to put the home side in front at half time, before they repelled the Gilistas' efforts after the break to claim all three points.
Prior to that, Santa Clara's run of two back-to-back Primeira Liga victories came to an end on October 5, when they were beaten 1-0 by Moreirense at the Parque Joaquim de Almeida Freitas thanks of a 79th-minute strike from Bernardo Martins.
Sandwiched between the two league outings, Vasco Matos's men booked their spot in the fourth round of the Taca de Portugal on October 19 courtesy of a 1-0 victory over Campeonato de Portugal outfit Gondomar at the Estadio de Sao Miguel.
Having gained promotion from the Segunda Liga last season, Santa Clara have been impressive on their return to the top flight, claiming six wins from their first nine games to sit fourth in the standings, just one point and one place behind Benfica.
Os Acorianos now turn their focus to the Taca da Liga, where they will be looking to make their mark this season, having missed out on the tournament last term, when they were beaten on penalties by Tondela in the first qualifying round.
However, Wednesday's opening game pits Santa Clara against an opposing side who have won each of the most recent seven meetings between the teams and are unbeaten in 11 of their last 12 clashes since January 2012.
Benfica form (all competitions):
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Santa Clara form (all competitions):
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Team News
With his hat-trick against Rio Ave at the weekend, Turkish international Akturkoglu now has 15 goal contributions for club and country this season, and the summer signing will be one to keep an eye on.
On the injury front, Lage will be unable to call upon the services of 23-year-old forward Tiago Gouveia, who has been sidelined since sustaining a shoulder injury against Estrela in August.
He is joined on the club's injury table by Leandro Barreiro and teenage forward Gianluca Prestianni, who are currently recuperating from thigh and ankle injuries respectively.
Meanwhile, Santa Clara remain without the services of experienced defender Pedro Pacheco, who has been out of action since coming off with a severe knee injury back in May.
Frederico Venancio was forced off injured midway through the game against Gil Vicente and the 31-year-old, who has started all nine league games this season, is a doubt for Wednesday's clash.
Benfica possible starting lineup:
Trubin; Kabore, Silva, Otamendi, Carreras; Aursnes, Luis; Amdoubi, Akturkoglu, Beste; Cabral
Santa Clara possible starting lineup:
Batista; Ramos, Rocha, Lima; Calila, Ferreira, Firmino, Nunes; Lopes, Costa, Silva
We say: Benfica 3-0 Santa Clara
Fresh off the back of an emphatic victory over Rio Ave, Benfica will head into the midweek clash with confidence as they look to launch their cup quest on a high. While we expect Lage to rest some big-name players, As Aguias boast the firepower needed to get the job done and we are backing them to extend their dominance over Santa Clara.