Liverpool, one of four English Premier League teams in this week's first knock-out round, now have the Champions League as their last hope of silverware this season.
Chelsea are also in action Tuesday where they take on Greek side Olympiakos in Piraeus, while nine-time European champions Real Madrid travel to AS Roma, second behind Inter in the Italian league.
In the evening's other first-leg game, Porto return to Gelsenkirchen - scene of their 2004 Champions League final triumph over Monaco - to play Schalke 04, the German Bundesliga's only team left in the competition.
For five-time European champions Liverpool and their Spanish manager Rafael Benitez much is now at stake as they meet runaway Italian league leaders Inter at Anfield.
The Reds, who won the Champions League in 2005, were humbled by Championship side Barnsley on Saturday, and face a battle to finish even fourth in the league for a Champions League berth.
British press reports say Benitez is fighting for his future at the club and his position will be reviewed at the end of the season.
But the manager - who has taken Liverpool to two European Cup finals in his three full seasons at Anfield - says he does not need another Champions League title to prove himself.
Liverpool, however, will need a vastly improved performance against Inter to have any chance of progressing.
"They look like running away with their title and are keen to win this trophy after watching AC Milan do that against us last season," defender Jamie Carragher told the club's website.
"It will be a big test for us and we will have to up our game a level or two to get through. Making a good start in the tie at home, though, is crucial."
For all the European pedigree of both clubs, Liverpool and Inter have met only once before in the European Cup when Inter won 4-3 on aggregate in 1965 on the way to winning the trophy for the second season in a row - the last time they won Europe's top crown.
The Italian champions are in good spirits after a 2-0 win over Livorno on Saturday put them 11 points clear in Serie A.
But president Massimo Moratti warns that Liverpool are "the classic Champions League team" who give their best when in difficulties.
"I can't tell if the recent defeat they suffered in the FA Cup is a favourable event for us or it increases our difficulties as it stimulates a reaction," he said.
Chelsea meanwhile head to Greece with midfielder Frank Lampard and captain John Terry recovered from long-term injuries. Forward Didier Drogba, who missed Saturday's 3-1 FA Cup victory over Huddersfield with a knee problem, should also return.
Chelsea manager Avram Grant warned Chelsea not to be complacent about the Greek champions.
"You may think this looks easy on paper, but it could be very difficult," he said. "We must not underestimate Olympiakos and their supporters are fanatical for the team."
Real Madrid have to cope with a long injury list for the trip to AS Roma. Coach Bernd Schuster will be without injured Christoph Metzelder, Pepe, Marcelo, Wesley Sneijder and Javier Saviola.
Gabriel Heinze and Ruud Van Nistelrooy are fit again, but striker Raul Gonzalez is struggling after taking a heavy blow to his left leg in Saturday's shock defeat 2-1 away to lowly Betis.
Schalke need to bounce back from a surprise 2-1 home defeat to Wolfsburg for their first-leg encounter against Porto.
Schalke striker Gerald Asamoah, the only player to have taken part in the club's three Champions League campaigns (2001/02, 2005/06 and 2007/08), said both teams had an equal chance of going through.
"Porto don't have a big name like Barcelona or Real Madrid but it is a team with international experience who play nearly every year in the Champions League," he told the club website.
"The Portuguese have a lot of strong individual players and we have to put in a top performance if we want to reach the next round."