The cauldron of San Siro will host both clashes, with the decisive second leg to come next Tuesday.
Despite being left in Napoli's wake in Serie A this season, both clubs enter the first leg on the back of impressive wins domestically on Saturday.
Milan beat Lazio 2-0 here at San Siro, while Inter beat Roma in the Italian capital by the same scoreline, to strengthen both side's hopes of finishing in the Serie A top four.
Here, Sports Mole looks at the head-to-head record between the two sides before the Derby della Madonnina double header to come.
Being two of Italy's and Europe's footballing powerhouses, the clubs have met on no fewer than 235 occasions, with their two Serie A meetings every season being notable dates on the calendar.
Inter have the slight edge in the head-to-head record, winning 87 times to Milan's 79, with a further 69 draws.
In the Champions League though it is a very different story, as Inter have failed to win any of the four meetings between the sides, during the knockout rounds in 2003 and 2005.
With 19 Serie A titles apiece, and 10 Champions League crowns between them, both have an illustrious honours list, but only once in history have the sides faced each in a major final, with Milan coming out on top in the 1977 Coppa Italia.
The clubs have traded blows in recent meetings, with both coming out on top in important clashes over the last few years.
There has already been a big clash between the sides this season, when the two met in the Italian Super Cup back in January, with the Nerazzurri coming out on top with a convincing 3-0 win in Riyadh.
That was the second time in the space of a year that Simone Inzaghi's side beat their bitter rivals by the same scoreline, also doing so in last season's Coppa Italia semi-final second leg, on their way to lifting the cup in the final in Rome.
It was win in favour of the Rossoneri that ultimately played a huge part in determining where Italy's biggest honour went last season though, when a dramatic late double from Olivier Giroud saw Milan beat Inter 2-1 to give them the upper hand in the Serie A title race, before Stefano Pioli's side went on to win the Scudetto.
The current crop of players in both sides have served up some classic encounters, but the early 2000s produced some of the most memorable between the clubs in recent history.
As previously mentioned, Inter failed to win any of the Champions League clashes between the sides when they met in the 2003 semi-finals and the 2005 quarter-finals.
Milan beat Inter on away goals at this stage in 2003, before the 2005 tie went down in history following crowd trouble which saw the second leg abandoned.
With Inter 3-0 down on aggregate, their supporters launched fireworks and flares on to the field, one of which hit Milan goalkeeper Dida, leading the referee to order the players off the pitch and call the game off.
The crowd trouble at San Siro spawned one of football's most memorable images, with Inter's Marco Materazzi and Milan's Rui Costa standing side-by-side watching the ensuing chaos.
Milan therefore progressed on both occasions and would reach both finals too, beating Juventus at Old Trafford in 2003, before their famous collapse against Liverpool in Istanbul in 2005.
The Rossoneri would avenge that defeat by becoming Champions of Europe again in 2007, but that same season they were humbled in front of their own supporters by Inter in Serie A.
An Inter side managed by Roberto Mancini flew out of the blocks and led 3-0 before Milan mounted a late comeback but just fell short, losing 4-3 in a pulsating encounter.
One of the most famous scorelines ever between the sides came in November 2001 though, when Milan hammered Inter 6-0 in front of furious Nerazzurri supporters in one of the club's most embarrassing results of their history.
With there being very little between the sides at the moment, as just three points separate the sides in Serie A, such a one-sided outcome looks unlikely in this hotly-anticipated tie.
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