After taking four points from Barcelona across two epic encounters, Inter can seal progress with a third win from five Group C games; Plzen are out of contention but could still snatch a Europa League spot via an improbable turn of events.
Match preview
Following their sluggish start to the season, a recent resurgence has seen Inter claim four wins from their last five matches, including a pair of memorable duels with revamped Barcelona.
A fortnight ago at Camp Nou, the Nerazzurri were denied victory only by Robert Lewandowski's late equaliser, after they had scored three times in the second half to come within touching distance of a famous win and a guaranteed place in the last 16.
Goals from Nicolo Barella, Lautaro Martinez and substitute Robin Gosens seemed set to give Inter back-to-back victories over their rivals for Group C's second spot, behind runaway leaders Bayern Munich, but even their 3-3 draw sees them hold a head-to-head advantage. That means they can assure a precious last-16 place with a win this week.
Indeed, they will still go through if they draw and Barcelona do not win - or, should Xavi's men lose to Bayern, Inter effectively have a free pass to the latter stages.
Simone Inzaghi will want to ensure that his side do not require assistance from the Bundesliga champions, and having lost only two of their last nine group matches in the Champions League - against eventual winners Real Madrid last year and Bayern this autumn - precedent suggests they can get the job done.
Inter's only previous meeting with Plzen was on matchday two, when they came away from the Czech Republic with a 2-0 victory, and an in-form Nerazzurri are expected to prevail once again.
Following wins over Sassuolo and Salernitana, Inzaghi's men most recently came out on top in a thriller to match events at Camp Nou: Saturday's spectacular 4-3 victory at Fiorentina saw Henrikh Mkhitaryan bundle home a winner in the fifth minute of stoppage time.
Now requiring snookers to even take third place in an exceptionally difficult group, Plzen will have to make history in order to stay in the mix come next week's final matchday: no Czech side has won away to a Serie A club throughout 10 previous Champions League or European Cup games.
Not only that, but Plzen have lost three of their four fixtures in Italy and travel to Milan on this occasion without a point to their name after four matches. As well as losing at home to Inter, the Czech champions have been beaten twice by Bayern (5-0 and 4-2) and were thumped 5-1 at Camp Nou.
As a result, they are already unable to reach the last 16 but can theoretically finish third and reach the Europa League. More likely, they will be confirmed in last place if they lose, or if they draw and Barcelona avoid defeat - or whatever happens at San Siro should the Catalans win.
Following their chastening experiences this year, Plzen have now lost 15 of their 22 group games in Europe's top club competition - of those clubs to have played at least 20 times, only Dinamo Zagreb have a higher percentage of defeats than their 68%.
Even retaining the ball has been beyond Michal Bilek's side so far, as they have averaged just 28% possession; that represents the lowest share since such records began in 2003.
In the Czech First League, Plzen have won each of their last three matches to sit four points clear at the summit, so look well set to defend their domestic crown on the back of 33 league games without defeat. However, they suffered a calamitous cup exit due to a 3-2 defeat at third-tier FC Hlucin last Wednesday.
They will now have to pull off a similarly seismic shock at San Siro if they are to prolong their latest European adventure.
Inter Milan Champions League form:
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Inter Milan form (all competitions):
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Viktoria Plzen Champions League form:
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Team News
Though midfield maestro Marcelo Brozovic remains unavailable due to a thigh injury - Henrikh Mkhitaryan should deputise for the Croatian again - Inter can include Romelu Lukaku in their squad on Wednesday.
The on-loan striker returns following a six-week absence, but should start on the bench, so Simone Inzaghi must choose between Edin Dzeko and Joaquin Correa to partner in-form forward Lautaro Martinez in attack.
Since his Champions League debut in 2018, the latter has scored more goals for the Nerazzurri than any other player (eight). However, the last one at San Siro came some three years ago.
Midfielder Roberto Gagliardini should also be back in the fold, but Nicolo Barella and Hakan Calhanoglu are expected to form the hosts' central trio along with weekend match-winner Mkhitaryan.
Meanwhile, Plzen made several changes on Saturday after losing to part-timers in the Czech Cup, and a strong side started the 3-1 win over Banik Ostrava.
Jan Kliment - who scored against Bayern last time out in the Champions League - and Tomas Chory may find their strike partnership broken up, though, as Michal Bilek reverts to a lone striker away from home in Europe; Fortune Bassey is also in contention to feature up front.
Long-serving veteran Lukas Hejda captains the side from centre-back in a probable 4-2-3-1 formation.
Inter Milan possible starting lineup:
Onana; Skriniar, De Vrij, Bastoni; Dumfries, Barella, Calhanoglu, Mkhitaryan, Gosens; Martinez, Dzeko
Viktoria Plzen possible starting lineup:
Stanek; Havel, Hejda, Pernica, Jemelka; Kalvach, Bucha; Kopic, Vlkanova, Mosquera; Chory