It will be just the second Clasico of the 2018-19 campaign and Barcelona recorded a thumping 5-1 win when the pair locked horns at Camp Nou in La Liga back in October.
It would be fair to say that the Copa del Rey has been extremely kind to Barcelona in recent years. Indeed, the Catalan giants landed their 30th crown last season and have lifted the trophy in each of the last four campaigns.
Barcelona have also been present in all but one of the last eight finals and will be looking to secure an advantage on Wednesday night ahead of the return match at the Bernabeu later this month.
Their progression to the semi-finals of this season's Copa del Rey has taken them past Cultural Leonesa, Levante and Sevilla. It has been far from straightforward, however, with Ernesto Valverde's side losing the away legs at both Levante and Sevilla before having to turn things around on home soil.
A 6-1 win over Sevilla on January 30 saw Barcelona ease into the semi-finals, but they will enter this match off the back of a 2-2 draw with Valencia at Camp Nou in La Liga. It was the first time that Barcelona had failed to win in the league since the end of November, but they remain top of the table on 50 points.
Barcelona have a tough trip to Athletic Bilbao in the league this weekend, before hosting Real Valladolid on February 16. The Spanish champions will then travel to Lyon for the first leg of their last-16 Champions League clash ahead of a trip to Sevilla in the league on February 23.
Valverde's team have been impressive this season, but it would be fair to say that they have had to rely on the brilliance of Lionel Messi to escape a number of dangerous situations in recent months.
The Copa del Rey is third on the list of priorities for Barcelona this season, but the fact that the semi-final is against Madrid means that the Catalan giants will be desperate to progress.
It will be the first time that Barcelona have locked horns with Madrid in the Copa del Rey since the final of the 2013-14 competition, where Los Blancos recorded a 2-1 victory to claim the last of their 19 trophies in the competition.
Recent form: WWLWLW
Recent form (all competitions): WWLWWD
There is no question that Madrid will arrive at Camp Nou in a much better place than they were in October, when they suffered a 5-1 defeat to the Spanish champions. There has been a change of manager since then, with Julen Lopetegui sacked following a poor start and Santiago Solari now in charge of the club.
The Whites have not been without their problems under Solari, but things are looking up with a run of five straight wins in all competitions. Indeed, they will enter this match off the back of a 3-0 victory over Alaves, which has seen them move to within two points of second-placed Atletico Madrid in Spain's top flight.
It is a huge period of the season for Madrid when considering that they will follow the clash with Barcelona by visiting Atletico in the league this weekend. Solari's team then face a trip to Dutch giants Ajax in the first leg of their last-16 Champions League clash on February 13.
Los Blancos have enjoyed incredible European success in recent years, but domestic trophies have been harder to find. As mentioned, they have not won the Copa del Rey since 2014 and have actually only triumphed in the competition on two occasions since 1993, which does seem incredible for a team of their ilk.
Confidence has returned in recent weeks, however, and they have also managed to recover a number of key players from injury. Madrid will be looking forward to visiting Barcelona on Wednesday night, which would not have been the case in the early stages of 2019 when they were struggling for results.
In terms of progression to the semi-finals, Solari's side have overcome Melilla, Leganes and Girona. They scored seven times against Girona in the quarter-finals and will be eyeing a final against either Real Betis or Valencia.
Nothing will be won on Wednesday night, but Madrid would fancy their chances of finishing the job in the second leg on home soil if they manage to pick up a positive result at Camp Nou.
After a strong run of recent form, it would be fair to say that the clash in Catalonia will give a good indication of how far the European champions have come in the last few weeks.
Recent form: WWWLWW
Recent form (all competitions): LWWWWW
Jasper Cillessen would have started this match between the sticks had he been fit, but the Dutchman will miss out with a muscular injury. As a result, Marc-Andre ter Stegen will play in the Copa del Rey for the first time this season.
Rafinha and Samuel Umtiti are also definitely out, while Barcelona have some concern over Messi. The Argentine picked up a thigh problem in the latter stages of the clash with Valencia, but should be available to start despite not taking part in his team's main training session on Monday.
Ousmane Dembele has recently recovered from an ankle problem, but the Frenchman is now believed to be suffering with tonsillitis, which makes it difficult to believe that he will be thrown into the starting XI, although the attacker could make the squad.
Sergio Busquets will also return for Barcelona having missed the clash with Valencia at the weekend through suspension.
As for Madrid, Solari has had to deal with a fairly lengthy injury list this season, but a number of players have returned to fitness in recent weeks. As a result, the Spaniard will have a tough task picking his team for El Clasico.
Dani Carvajal and Raphael Varane both missed the clash with Alaves through suspension but are expected to return to the XI here. Meanwhile, Marcelo could also take the place of Sergio Reguilon at left-back.
Lucas Vazquez's absence from the clash with Alaves suggests that the Spaniard will start and he will definitely be joined by Karim Benzema, who has 18 goals for the season. Benzema has netted four times in four Copa del Rey matches this term, meanwhile, and will be a serious threat to Barcelona.
Gareth Bale and Marco Asensio will both be eyeing the other spot in attack having returned from injury, but it seems likely that Vinicius Junior's excellent form will see the 18-year-old handed yet another starting role down the left.
Barcelona possible starting lineup:
Ter Stegen; Semedo, Pique, Lenglet, Alba; Arthur, Rakitic, Busquets; Coutinho, L Suarez, Messi
Real Madrid possible starting lineup:
Navas; Carvajal, Varane, Ramos, Marcelo; Casemiro, Kroos, Modric; Lucas, Benzema, Vinicius
Head To Head
As mentioned, the pair have only met once this season and that was Barcelona's 5-1 league win back in October.
Barcelona have enjoyed a lot of recent success in El Clasico, but Madrid have a recent Camp Nou victory to their name, having recorded a 2-1 success in April 2016.
In all, Wednesday will bring their 239th competitive match. Madrid lead the head-to-head 95 wins to Barcelona's 93, with the remaining 50 games finishing level.
We say: Barcelona 1-1 Real Madrid
It should be a fascinating clash at Camp Nou on Wednesday night. Barcelona are the favourites, but we fancy an in-form Madrid to pick up a 1-1 draw ahead of the return fixture in the Spanish capital.