Last season's runners-up, Inter are flying high at the top of Serie A; meanwhile, Atleti stormed through the group stage to reach the knockout rounds once again.
Match preview
Having started 2024 with eight wins on the spin, Inter can consider themselves in peak form ahead of their return to the Champions League, in which they have proven to be one of Europe's elite teams over the past two seasons.
The Nerazzurri have lost just one of their last 13 games in UEFA's top club competition - that lone defeat coming against Manchester City in the 2023 final - while keeping no fewer than eight clean sheets in the process.
Since finishing second in Group D, just behind Real Sociedad, Simone Inzaghi's side have suffered only one significant setback - dramatically losing in extra time to Bologna in the Coppa Italia - and the new year has seen them reach new heights.
Inter swept to a third successive Supercoppa Italiana by beating both Lazio and Napoli, before victory in the Derby d'Italia helped keep title challengers Juventus in the rear-view mirror; scoring four times in their last two outings then capitalised on Juve's faltering form.
Nine points clear atop Serie A following Friday's 4-0 defeat of rock-bottom Salernitana - which saw captain and top scorer Lautaro Martinez add further to his impressive goal tally - the Milan giants are also among the favourites to reach June's Champions League finale at Wembley.
However, their first knockout meeting with a Spanish side since the 2010 semi-finals - when Jose Mourinho's men eliminated Pep Guardiola's Barcelona en route to an unforgettable treble triumph - comes against opponents that always pose a threat, partly thanks to the wily coaching of an ex-Inter midfielder.
Under Diego Simeone, Atletico Madrid have won five of six previous knockout matches against Italian clubs in continental competition, and the Spanish side now seek their sixth at San Siro, where they have yet to take on Inter.
The teams' only competitive meeting was in the 2010 UEFA Super Cup, won by Los Colchoneros thanks to goals from Sergio Aguero and the late Jose Antonio Reyes, but now another heavyweight contest awaits.
While Atleti trail behind city rivals Real Madrid in La Liga, where they occupy fourth place, Simeone's side blitzed their way through Group E during the autumn - scoring 17 Champions League goals this season is already their best tally for a decade.
Alvaro Morata notched five in six games - the most by a Spanish player since Atletico's run to the final in 2014 - as Lazio, Feyenoord and Celtic were swept aside in an unbeaten group-stage campaign; however, they have been bedeviled by inconsistent form since.
Warming up for the trip to Milan with a 5-0 drubbing of Las Palmas saw them end a three-game streak without victory and continue a magnificent run of results at the Metropolitano this season: 12 wins and one draw represents by far the best home record in Spain's top flight.
On the road, though, Atletico have won only four times in the league, and they are sure to be put under pressure by an Inter side that rarely loses on home soil.
Inter Milan Champions League form:
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W
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D
Inter Milan form (all competitions):
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W
W
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W
W
Atletico Madrid Champions League form:
D
W
D
W
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Atletico Madrid form (all competitions):
W
W
D
L
L
W
Team News
After regular wing-backs Matteo Darmian and Federico Dimarco were rested on Friday, both should return to Inter's starting XI in midweek, while defensive rock Francesco Acerbi could recover from a calf injury sustained in the recent win over Roma.
Davide Frattesi was an unused substitute in Salerno, having previously been troubled by a thigh problem, so Juan Cuadrado - who was removed from Simone Inzaghi's Champions League squad after undergoing Achilles tendon surgery - is the only player occupying the Nerazzurri's treatment room.
Therefore, the hosts will line up in a familiar 3-5-2 formation, with Hakan Calhanoglu patrolling midfield, and Marcus Thuram joining Lautaro Martinez up front.
The latter has netted 12 Champions League goals to date, behind only Adriano (14) and Julio Cruz (13) on Inter's all-time list; his strike against Salernitana also saw 'El Toro' become just the third player to score 20 Serie A goals for the club in three successive seasons - and the first for 70 years.
Atletico boss Diego Simeone will meet Inzaghi - with whom he won the Italian double in 1999-2000, as teammates at Lazio - faced by a more significant absence list than his opposite number.
Gabriel Paulista, Cesar Azpilicueta, and long-term absentee Thomas Lemar are all sidelined, while Alvaro Morata was withdrawn at half-time against Sevilla due to a knee injury that also saw him sit out Atleti's weekend win.
Even without Morata, the visitors still have several options in attack, as Antoine Griezmann has scored 18% of the club's Champions League goals total to date and Memphis Depay boasts six strikes from his last nine appearances; meanwhile, Marcos Llorente and Angel Correa both bagged braces against Las Palmas.
Inter Milan possible starting lineup:
Sommer; Pavard, Acerbi, Bastoni; Darmian, Barella, Calhanoglu, Mkhitaryan, Dimarco; Thuram, Martinez
Atletico Madrid possible starting lineup:
Oblak; Savic, Witsel, Hermoso; Llorente, Barrios, De Paul, Koke, Lino; Griezmann, Depay