Inter can start Lautaro Martinez with Joaquin Correa and Henrikh Mkhitaryan standing in for Marcelo Brozovic, while Barcelona look to Robert Lewandowski, Raphinha and Ousmane Dembelé.
It kicks off at the Stadio Giuseppe Meazza, also known as San Siro, at 20.00 UK time (19.00 GMT).
This is potentially a decider in the race to see who qualifies for the Champions League Round of 16, because both teams are on three points, behind runaway leaders Bayern Munich on six.
Their domestic form has been wildly different lately, as the Nerazzurri lost four of their last six Serie A games, whereas Barça are top of LaLiga winning six in a row.
Inter have not beaten Barcelona since the legendary 3-1 Champions League semi-final here in March 2010, on their way to the Treble under Jose Mourinho, followed by one draw and four defeats.
Romelu Lukaku and Marcelo Brozovic are still out injured, but at least Lautaro Martinez can start despite a small muscular issue, with Joaquin Correa and Mkhitaryan stepping in rather than Edin Dzeko and Kristjan Asllani.
Barcelona have problems too, losing Memphis Depay and Frenkie de Jong on international duty, joining Hector Bellerin, Ronald Araujo and Jules Koundé to injury.
Champions League stalwart Lewandowski leads the attack with Raphinha and Dembelé, but Xavi still rotates his squad from the side that beat Real Mallorca 1-0 on Saturday.
Inter: Onana; De Vrij, Skriniar, Bastoni; Darmian, Mkhitaryan, Calhanoglu, Barella, Dimarco; Correa, Lautaro Martinez
Barcelona: Ter Stegen; Sergi Roberto, Garcia, Christensen, Marcos Alonso; Gavi, Busquets, Pedri; Raphinha, Lewandowski, Dembelé
Ref: Vincic (SVN)