
Last year's beaten finalists opened with a draw against Porto before suffering a surprise home loss to Marseille, who now top the group with a maximum six points ahead of the visit of Porto.
Rafa Benitez will be without Fernando Torres and injured defender Daniel Agger in Turkey, but hopes to have Spaniards Xabi Alonso back.
Striker Torres also missed the weekend win over Everton because of his ongoing thigh problem, while midfielder Alonso is ready to return after just over five weeks out with a metatarsal injury.
"It's absolutely a must-win game," Alonso said. "It is massive because if we are to recover and get in the top two of the group, we have to win this match.
"It's very important, probably even more important than the three points on Saturday (from the 3-1 win over local rivals Everton in the English Premier League."
Group B leaders Chelsea will be without injured defenders John Terry and Ashley Cole for their match against Schalke 04.
The Blues have lifted their game since gaining just two points from four league games last month, and forward Joe Cole believes victory over the German side would put them well on the way to qualifying for the next stage.
"Schalke now is an important game and if we win it'll put us in pole position in the group," he said.
"It'd be nice if we can take the points and be a bit more comfortable in the Champions League, so it's a big game."
Chelsea lead group B with four points, one clear of Schalke and Valencia who face Rosenborg in the other group game.
Valencia will be without Edu, Manuel Fernandes and Villa but the good news is that winger Vicente Rodriguez is finally fit again after three years of torment with his battered right ankle.
"We really have to win in Norway," said Valencia captain David Albelda, "otherwise we could have problems in this group."
Real Madrid should have few problems at home to Olympiakos in group C, despite their own injury problems.
Arjen Robben and Gabriel Heinze came back from national team duty with Holland and Argentina with muscle injuries. Defender Pepe is still not fit.
Real coach Bernd Schuster was furious with Robinho and Julio Baptista coming back late from Brazil and had no choice but to leave them out of the team which lost 2-1 to Espanyol on Saturday.
The same as Ronaldinho, though, they will be pardoned for the European match - though more out of expediency than forgiveness.
Real are joint top of the group with Olympiakos, both on four points. Lazio are away to Werder Bremen in the other group game.
In Group D, European champions AC Milan welcome Shakhtar Donetsk hoping to end a crisis that worsened at the weekend after a 1-0 home defeat to Empoli.
Milan's woes continued Tuesday with the news that defender Marek Jankulovski will undergo knee surgery this week that will keep him sidelined for no less than two months.
But Brazil star Kaka returns from a knee injury, while his compatriot Ronaldo remains sidelined with a lingering muscular pain.
"We have great difficulties," said Milan captain Paolo Maldini, who returned at the weekend after a five-month absence. "At the moment, the only thing to say is that we must play game by game."
The Ukrainian side lead Group D with a maximum six points, three clear of Milan and Celtic, who face Benfica.
DPA