There is no place for Cristiano Ronaldo after the Portuguese went off with an injury at half-time against Barcelona on Sunday, while Keylor Navas, Marcelo, Luka Modric, Toni Kroos, Isco and Raphael Varane are not included either.
Los Blancos were due to face Sevilla on April 21, but the match was postponed due to the Andalusians' involvement in the Copa del Rey final against Barcelona that weekend.
Zinedine Zidane's side, fresh from drawing 2-2 in a controversial Clasico clash at Camp Nou on Sunday, can catch city rivals Atletico with a win in this fixture, with Diego Simeone's mean currently three points ahead of Real with one more match played.
Madrid's main focus, of course, will be the Champions League final against Liverpool later this month. But here, Goal takes a look at everything you need to know ahead Wednesday's match at the Sanchez Pizjuan...
Real Madrid injuries
Ronaldo is out are suffering a sprained ankle against Barcelona on Sunday, which saw the Portuguese withdrawn at half-time in the Clasico. Meanwhile, Dani Carvajal is not quite ready to return from injury. Isco is fit again, but has not been included in the squad for Wednesday's game.
Real Madrid suspensions
Gareth Bale is banned for the midweek match after he was booked in the 2-2 draw in Barcelona.
Real Madrid potential starting line-up
This is the second of three fixtures in the space of a week for Real Madrid and with the Champions League final ahead, Zidane will not want to risk any of his players.
Ronaldo (injured) and Bale (suspended) are out anyway, so there are likely to be starts for Borja Mayoral, Lucas Vazquez and Marco Asensio, with Dani Ceballos also set to feature as Isco is not in the squad despite returning to fitness this week.
Youngster Achraf Hakimi should start at right-back in the absence of the injured Carvajal, with Nacho moving inside to central defence and Theo Hernandez deputising for Marcelo on the left.
Mateo Kovacic and Casemiro should start in central midfield, while Karim Benzema is in the squad and the French forward looks set to be a substitute in Seville.
Sevilla team news
Sevilla parted company with coach Vincenzo Montella after their recent 2-1 defeat at Levante and former boss Joaquin Caparros has taken over for the rest of the season.
His first game was a 1-0 win over Real Sociedad and the aim is to qualify for European competition, for which they will need to finish in seventh place.
The Andalusians are currently eighth, a point behind Getafe, but with a game in hand over the Madrid-based outfit.
Jesus Navas is doubtful for Wednesday's game, while Pablo Sarabia is suspended.
TV channel & kick-off time
Sevilla versus Real Madrid kicks off at 9:30pm local time on Wednesday and will be shown live in the United Kingdom (UK) on Sky Sports Football (via the red button) from 8:30pm BST.
In the United States (US), the match is live on beIN Sports and kicks off at 3:30pm ET.
Best Opta match facts
Sevilla have only won four of their last 16 league games against Real Madrid (they have lost the other 12), but all four wins have come at the Sanchez Pizjuan.
Those four La Liga away defeats at Sevilla since 2012-13 mean Madrid have lost more against the Andalusians than versus any other opponent in that period.
Sevilla have only won one of their last eight La Liga games (with three draws and four defeats in that time).
Karim Benzema has only scored five goals in La Liga this season, his worst goalscoring tally in a single campaign for Real Madrid.
Sergio Ramos has scored six goals against his former team in all competitions, more than against any other team.