In a quick-fire reprise of their Europa League semi-final just two months ago, the Italian giants take on the conquerors of Real Madrid at the Olympic Stadium.
Shakhtar Donetsk begin their 'home' Champions League campaign, in the Ukrainian capital, buoyed by the stunning opening night upset of a decidedly off-colour Real Madrid.
With confidence now soaring, they will have a sweet dose of revenge in mind, given their heavy defeat by Inter in last season's Europa League final tournament.
Incredibly, Shakhtar were 3-0 up at half-time in their opening Group B fixture at Estadio Alfredo Di Stefano and, though the home side fought back in the second half, they held out for a deserved 3-2 victory.
It was all the more incredible a feat, as Luis Castro's fearless team contained eight players under the age of 23 after an ill-timed COVID-19 outbreak pre-match.
Meanwhile, Inter needed a 90th-minute strike from go-to goal-getter Romelu Lukaku to salvage a 2-2 opening draw at home to Borussia Monchengladbach. It was Lukaku's second of the night; remarkably he has now scored in nine successive matches in UEFA club competition.
One of those games included his late double in the 5-0 thumping of the Ukrainian champions in Dusseldorf. Now, the same teams meet again in what promises to be a closely fought Group B.
Despite that opening victory in Madrid, Castro's men have won only three of their last 14 Champions League matches, losing five.
Inter have fared no better, having won only two of their last 11 games at the elite continental level. They are, however, undefeated in their nine European encounters with Ukrainian sides, winning the last four.
On Saturday, Antonio Conte's side won for the first time in four games in all competitions, Danilo D'Ambrosio and the ever reliable Lukaku getting the goals in a 2-0 Serie A success at Genoa. The Belgian marksman now has 10 goals in nine games for club and country so far this term and has scored in each of his last five outings.
Tuesday's hosts could only draw their home league game with Vorskla, even though their opponents went down to 10 men early in the second half. Unsurprisingly, the euphoric high of last Wednesday was curtailed by rather more pedestrian matters in a domestic league which they have utterly dominated in recent years.
Although the atmosphere will not be at full force for the visit of Inter - considering Shakhtar's enforced re-location from the Donbass Arena and the fact that only up to 30% of capacity can be filled by local fans - it promises to be a more closely contested encounter than last time.
Shakhtar Donetsk Champions League form: W
Shakhtar Donetsk form (all competitions): WDWWD
Inter Milan Champions League form: D
Inter Milan form (all competitions): WDLDW
Achraf Hakimi's 'false positive' test before last week's opener was followed by a subsequent negative result and, after coming off the bench at the weekend in Genoa, he should return to Conte's starting XI.
Alexis Sanchez was replaced at half time against Gladbach after injuring his right thigh and was absent on Saturday, while Stefano Sensi has missed Inter's last two games with a thigh problem - offering hope to Christian Eriksen of a rare start.
Shakhtar Donetsk possible starting lineup:
Trubin; Dodo, Bondar, Khocholava, Kornienko; Maycon, Tete, Marlos, Alan Patrick, Solomon; Dentinho
Inter Milan possible starting lineup:
Handanovic; D'Ambrosio, Bastoni, Kolarov; Hakimi, Barella, Vidal, Eriksen, Perisic; Martinez, Lukaku
We say: Shakhtar Donetsk 1-2 Inter Milan
Inter got back on track with a regulation victory at Marassi, after a demoralising derby defeat had threatened to derail their campaign before it had really begun and, with Lukaku still unstoppable, can now register a first Champions League win of the season.
Though Shakhtar pulled off one of the shocks of the decade - admittedly it is less than a year old, but there have been plenty of shocks from all angles - repeating the feat may be just a step too far for Luis Castro's depleted side.