However, both clubs have endured underwhelming starts in Group B and, rather incredibly, sit outside the top two at this midway point.
Inter Milan's stuttering start to the season looked set to continue when they played host to Torino at the weekend, with the visitors storming into a 2-0 lead just after the hour mark as Simone Zaza drew first blood before a Cristian Ansaldi penalty put Torino in control at San Siro.
However, Antonio Conte's formidable attacking options soon turned the game on its head as Alexis Sanchez, Lautaro Martinez and Romelu Lukaku (2) ensured that the Nerazzurri's winless run in all competitions would not stretch to five matches as Inter ran out 4-2 winners in a pulsating encounter.
However, Conte is still yet to witness his talented crop march to victory in Europe's elite competition, as Inter - who triumphed in the Champions League as recently as 2010 - sit rock bottom of Group B with only two points taken from a possible nine thus far.
Not even Borussia Monchengladbach or Shakhtar Donetsk supporters could have envisaged their clubs occupying the top two spots while European giants Inter and Real languish in fourth and third respectively, but having mustered just two wins from their last nine in all competitions, Conte will need his players to be firing on all cylinders if they are to register their first Champions League victory of the campaign this week.
In their first continental game of the season at San Siro, Inter were once again indebted to the goals of Lukaku as his double rescued a point against Monchengladbach, and the 27-year-old will be eyeing his 10th of the season in all competitions against Los Blancos.
Real Madrid's recent domestic exploits are nothing to write home about either, with the Spanish champions held to a 1-1 draw by Unai Emery's high-flying Villarreal in their first game back following the international break.
A Mariano Diaz header broke the deadlock after just two minutes, but Gerard Moreno chalked up his fifth top-flight goal of the season from 12 yards to ensure that the spoils were shared in a tie which Zinedine Zidane admitted was "two points dropped".
Two points is also what separates Real from their midweek opponents Inter in Champions League Group B, with Los Blancos finding themselves in the Europa League spot with one victory, one draw and one defeat from their opening three matches.
Goals have not been a problem for Zidane's side - who have notched up at least two in each European game so far - but Shakhtar are currently ahead of Real on head-to-head points, with the Ukrainian side not able to forget their historic 3-2 victory at the Estadio Alfredo Di Stefano in a hurry.
However, something has to give when Monchengladbach and Shakhtar meet a couple of hours before Inter and Real lock horns, and should the game between the top two end with the points shared, Real would leapfrog both teams into top spot with a first-ever victory on Inter Milan's turf.
The first meeting between Inter and Real earlier this month was packed with goals and excitement, and Zidane's men ultimately took the spoils in a 3-2 victory, with Rodrygo coming off the bench to net the winner for Los Blancos in that one.
Inter Milan Champions League form: DDL
Inter Milan form (all competitions): WDDLDW
Real Madrid Champions League form: LDW
Real Madrid form (all competitions): WDWWLD
Inter Milan trio Aleksandar Kolarov, Marcelo Brozovic and Daniele Padelli continue to self-isolate after returning positive coronavirus tests, while Stefano Sensi and Matias Vecino remain in the treatment room.
Martinez is also expected to occupy a spot up top after notching up one of his side's goals in their defeat to Real last time out, but there is unlikely to be any place in the team for Christian Eriksen, with the playmaker being linked with a move to Manchester United after being overlooked by Conte once again in the Torino win.
Marco Asensio started the win over Inter earlier this month and could come back into Zidane's first XI here, with Rodrygo and Vinicius Junior likely restricted to appearances from the bench once again.
Inter Milan possible starting lineup:
Handanovic; Skriniar, Bastoni, De Vrij; Hakimi, Barella, Vidal, Gagliardini, Perisic; Martinez, Lukaku
Real Madrid possible starting lineup:
Courtois; Carvajal, Varane, Militao, Mendy; Casemiro, Kroos; Asensio, Isco, Hazard; Diaz
We say: Inter Milan 2-1 Real Madrid
With both of these European powerhouses finding themselves in unfamiliar positions in Group B, both managers should be setting their teams up to attack, which will make for a fascinating spectacle for fans and neutrals alike. Martinez and Lukaku will certainly fancy their chances against an injury-hit Real defence, and while Zidane may be boosted by the returns of Casemiro and Militao, we think the hosts will eke out a vital win.