Los Blancos have only picked up one point from their two matches against Shakhtar Donetsk and Borussia Monchengladbach to sit bottom of the section, while Inter have drawn their two games to occupy third.
Madrid are actually on a four-game winless run in the Champions League, having also lost twice to Manchester City in the last-16 stage of last season's competition.
Zinedine Zidane's side would have been looking to open their 2020-21 challenge with a win against Shakhtar, but they suffered a 3-2 loss to the Ukrainian side on October 21, despite the fact that the visitors were without a number of key players due to a coronavirus outbreak.
Madrid find themselves bottom of the section with one point, but they will still fancy their chances of qualifying for the latter stages and will enter the match off the back of a 4-1 victory over Huesca on Saturday, which has left them top of La Liga with 16 points from their seven matches.
The capital giants have actually lost in the round of 16 in the last two seasons, but they are the most successful team in the history of this competition - winning 13 trophies - and will be determined to pick up a victory ahead of a difficult trip to San Siro in their next European clash at the end of November.
Inter, who reached last season's Europa League final, would have fancied their chances of picking up a healthy total from their first two matches in the section, but they were held to a 2-2 draw by Gladbach on October 21 before playing out a goalless draw with Shakhtar last week.
Antonio Conte's side now face arguably their two toughest matches in the section and disappointing results in their double-header with Madrid would place serious pressure on them ahead of their final two group matches away to Gladbach and at home to Shakhtar in the early stages of December.
Inter will also enter the match off the back of a 2-2 draw with Parma in Serie A on Saturday, which has left them in fifth position in the table, having won three, drawn two and lost one of their six matches this term.
The Italian giants have actually only won two of their last 12 Champions League matches, suffering five defeats, while their last two campaigns in this competition have ended in the group stage.
This will actually be the first time that Inter have faced Madrid in any European competition since the group stage of the 1998-99 Champions League, and the Serie A giants ran out 3-1 winners on home soil, having suffered a 2-0 defeat in the reverse match at the Bernabeu.
Real Madrid Champions League form: DWLLLD
Real Madrid form (all competitions): WLLWDW
Inter Milan Champions League form: WLWLDD
Inter Milan form (all competitions): DLDWDD
The Spanish club's issues at right-back have also intensified with Lucas Vazquez picking up a muscular problem against Huesca, meaning that Ferland Mendy could start on the right with Marcelo on the left.
Toni Kroos started on the bench at the weekend but should come into the XI on Tuesday night, while Eden Hazard got his name on the scoresheet on his return to the team against Huesca, and the Belgium international could again feature alongside Marco Asensio and Benzema as a front three.
Eder Militao will not be involved on Tuesday evening, though, having tested positive for coronavirus.
As for Inter, Romelu Lukaku is a huge doubt with a muscular strain, and it seems incredibly unlikely that the striker will even be fit to even make the bench, which would be a huge blow.
Lautaro Martinez is certain to start in the final third of the field, while he could be joined by Alexis Sanchez, with the Chile international being left out against Parma on Saturday with a view to being fit for this game.
Real Madrid possible starting lineup:
Courtois; Mendy, Varane, Ramos, Marcelo; Kroos, Casemiro, Valverde; Hazard, Benzema, Asensio
Inter Milan possible starting lineup:
Handanovic; D'Ambrosio, De Vrij, Bastoni; Hakimi, Barella, Brozovic, Vidal, Perisic; Sanchez, Martinez
We say: Real Madrid 2-1 Inter Milan
There is no downplaying the importance of this match as both teams look to record their first Champions League wins of the season. Lukaku's expected absence is a big blow for Inter, and we fancy Madrid to edge a very close encounter in the Spanish capital.