It will be only Real Madrid's second game, but anything but a victory could potentially lead to trouble for the rest of the season.
The world's richest sports club entered the season with high expectations but was held to a scoreless draw at newly promoted Sporting Gijon in the first round, while rivals Barcelona and Atletico Madrid got off to a winning start and opened an early lead in the standings.
Another setback at the Santiago Bernabeu could put new coach Rafa Benitez under pressure early in his stint with the club.
The team's slow start is already giving opponents added encouragement. Real Betis players said they will travel to Madrid more motivated after seeing Benitez's team struggle at Gijon.
"We saw that Sporting had a positive result against Real the other day," former Madrid goalkeeper Antonio Adan said. "It's difficult to do well at the Bernabeu, but if it was impossible we wouldn't even go there. Every year there is some type of surprise there, so why can't that happen to us?"
Betis opened with a 1-1 draw at Villarreal thanks to an equalizer by striker Ruben Castro near the end of the game at the Benito Villamarin Stadium.
Real Madrid's powerful attack led by Cristiano Ronaldo failed in the opener, missing chance after chance in Gijon. But Benitez's offense will be boosted Saturday by the addition of Karim Benzema, who is likely to be fit after nursing a muscle injury that kept him out of the first game. Gareth Bale, who had been doubtful because of a toe injury, is also set to play, keeping the attack at full strength.
"We know that this is just the beginning," Benitez said. "We have to keep improving."
Barcelona also will be making its home debut on Saturday, facing Malaga at the Camp Nou to try to keep its momentum going after a hard-fought 1-0 win at Athletic Bilbao.
Lionel Messi, who missed a penalty in the opening game, may be able to team-up with Neymar for the first time this season. The Brazilian forward has fully recovered after being diagnosed with the mumps.
Neymar was one of several injury-related problems that coach Luis Enrique has already faced this season. Right back Dani Alves is expected to miss Saturday's game because of a groin injury sustained against Athletic Bilbao, although Sergio Busquets should be fit after leaving that match with an ankle problem. Gerard Pique is out because of a suspension.
Barcelona has beaten Malaga in nine of their last 10 league meetings at the Camp Nou, but the lone loss came last season, a 1-0 defeat that allowed Real Madrid to open a four-point lead at the time. Barcelona eventually recovered to win the title.
Atletico Madrid won its home opener 1-0 against newcomer Las Palmas and now travels to face Sevilla, a team that could also be fighting at the top of the table by the end of the season.
A victory could be important as Diego Simeone's team faces a difficult stretch in the next few weeks. The surprise league winner two seasons ago, Atletico will host Barcelona in the third round before starting its Champions League campaign.
Brazil left back Filipe Luis, one of the team's best players in the opener, missed a practice this week but is set to play in Sunday's match.
In addition to Atletico and Barcelona, only three other teams won their first-round matches: Espanyol, Celta de Vigo and Eibar, the modest Basque club that is playing only its second season in the Spanish league.
Eibar tops the standings on goal difference thanks to its 3-1 win at Granada on Monday. Eibar will host Athletic Bilbao on Sunday.
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