This is the second consecutive campaign in which these two European giants, along with Ukrainian outfit Shakhtar Donetsk, have been drawn in the same group of the competition; Los Blancos beat the Nerazzurri home and away last season, including a 2-0 victory in Milan.
Since their triumphant 2009-10 Champions League campaign under Jose Mourinho, Inter have only ever progressed from the group stage on two occasions, and have qualified for the competition just five times.
The Nerazzurri had previously endured a difficult period in the 2010s with new ownerships and a plethora of managers at the helm, though stability and progress has clearly been noticed in recent seasons and the club are now hoping to reach the heights that they did over 10 years ago.
After winning their first Scudetto in over a decade last season, Inter have begun their title defence with impressive 4-0 and 3-1 victories against Genoa and Hellas Verona respectively, before playing out an entertaining 2-2 draw away at Sampdoria last weekend.
Simone Inzaghi's side were in front on two occasions, with first-half strikes from Federico Dimarco and Lautaro Martinez, though the hosts pegged them back twice to ensure the spoils were shared at the Luigi Ferraris Stadium.
Inter now turn their attention to Europe's elite club competition with an opening fixture against the team who will likely be their toughest opponent in the form of Real Madrid, a club they have actually beaten in four of their six competitive meetings on home soil.
Despite this impressive home record, the Nerazzurri have in fact lost four of their last five games against Los Blancos in a European competition, and will likely be in for a challenging evening on Wednesday.
Claiming points in midweek, however, would be highly beneficial for Inter's quest to reach the knockout stages and for them to potentially qualify as group winners.
Seeking their 14th Champions League crown and their first since 2017-18, Real Madrid remain as one of the tournament's favourites, though the competition around them has improved greatly and success this campaign could prove to be a challenge.
Under the tutelage of former boss Zinedine Zidane, Los Blancos finished top of their group last season – ahead of both Inter Milan and Shakhtar Donetsk – before beating Atalanta and Liverpool in the knockout stages. Real were ultimately sent packing by eventual champions Chelsea, losing 3-1 on aggregate in the semi-finals.
Los Blancos head into Wednesday's opening group-stage clash on the back of a 5-2 La Liga victory against Celta Vigo, which was the first game played at the Santiago Bernabeu in over 18 months.
Around 25,000 supporters certainly got their value for money, as they saw talisman Karim Benzema score a hat-trick, while Vinicius Junior and summer signing Eduardo Camavinga were also on the scoresheet.
Real, who have now climbed to the La Liga summit with 10 points from their opening four matches, have an impressive record against Italian opposition, winning 12 of their last 13 matches in the Champions League, including their previous two against Inter last season.
Head coach Carlo Ancelotti, who won the Champions League with Los Blancos in 2013-14, has the greatest win percentage (76%) of any manager at a single club in the competition's history who has managed at least 20 games.
The Italian will return to familiar territory on Wednesday night, with expectations from the board and supporters high, as they aim to kickstart their campaign with all three points.
Inter Milan defender Alessandro Bastoni is a doubt for Wednesday's match with a thigh injury, which he picked up on international duty with Italy earlier this month.
Inzaghi is unlikely to make too many changes to his starting lineup that played against Sampdoria, so central midfield trio Nicolo Barella, Marcelo Brozovic and Hakan Calhanoglu are all set to keep their places in the side.
Experienced striker Edin Dzeko is expected to lead the line in attack alongside Argentina international Martinez, though the latter's compatriot Joaquin Correa will also be pushing for a place in the first XI.
As for Real Madrid, Ancelotti could be without up to seven first-team players in midweek, including Gareth Bale, David Alaba, Toni Kroos and Luka Jovic, who all missed Sunday's win against Celta Vigo.
Bale (hamstring), Alaba (muscle overload), Kroos (groin) and Jovic (gastroenteritis) will all be assessed ahead of kickoff, though all four are unlikely to feature in Italy.
Left-back Ferland Mendy and midfielder Dani Ceballos – who have yet to play for Los Blancos so far this season – are two players who are unavailable for selection, as the pair are suffering with respective leg and ankle injuries.
Benzema, who needs just one more goal to move ahead of club legend Raul into outright fourth place on the all-time list of goalscorers in Champions League history, is expected to lead the line in attack and could be joined once again by wingers Eden Hazard and Vinicius Junior.
Inter Milan possible starting lineup:
Handanovic; Skriniar, De Vrij, Dimarco; Darmian, Barella, Brozovic, Calhanoglu, Perisic; Martinez, Dzeko
Real Madrid possible starting lineup:
Courtois; Carvajal, Militao, Nacho, Gutierrez; Valverde, Casemiro, Modric; Hazard, Benzema, Vinicius Jr
We say: Inter Milan 1-2 Real Madrid
Even though Inter have had success on home soil against Real Madrid, last season's encounter with the Spanish giants proved to be a challenge and another difficult game could be on the cards on Wednesday.
We expect goals from this blockbuster clash at the San Siro, though Ancelotti's men should have enough to take away all three points.
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