With defending champions CSKA Moscow in firm control of the top spot in Group E and the two sides even at 1-2, Olympiacos coach Pinhas Gershon believes that Wedneday's clash is do-or-die for both clubs.
"If we don't win, it's a disaster and we know this very well," Gershon said ahead of the match.
"The Serbians are coming to Piraeus as an underdog, but they need the win because if they lose they aren't going to qualify for the qauarter-finals."
Partizan Belgrade are at full-strength for the clash, while Olympiacos have lost big-man Ryan Stack for two months to injury and are still without Arvydas Macijauskas, who is yet to play this season.
Scoonie Penn torched Partizan for 27 points to lead Olympiacos to a 92-84 road-win in the Top 16 opener in Belgrade, but only scored 3 points against CSKA last week.
Still, memories of the earlier match make the visitors very wary of Penn's scoring prowess.
"We shall see if the opportunity is real, because we have two hard road games to play, but we have our own ambitions and we do believe in ourselves," said Partizan guard Milenko Tepic.
"I hope that Scoonie Penn shall be guarded better than in our first game in Belgrade, when he was key for Olympiacos."
DKV Joventut (1-2) will also try to stay alive in Group E when they host CSKA in Badalona.
The Spanish club are boosted by key CSKA injuries to David Vanterpool, who will miss Wednesday'a match, and star point guard Theo Papaloukas, who is questionable.
But Joventut will be without Czech scoring threat Lubos Barton , who has been ruled out of the rest of the Top 16 with a shoulder injury.
Pau-Orthez will be desperate for their first Top 16 win when they host Lottomatica Roma in a do-or-die game for the French club, who will be mathematically eliminated with a loss.
In another replay of the classic rivalry, Tau Ceramica host Maccabi Tel Aviv with the ability to clinch a place in the next round with a win and a possibility to secure the top seed in the group if Roma lose to Pau.
To add to the drama, Argentine star Luis Scola can become the Euroleague's all-time leading scorer with just seven points.
Maccabi, who beat their Spanish rivals in the Euroleague Final Four twice in the previous two seasons, will be hungry for revenge after TAU upset the 2005 champions 68-79 in the Top 16 opener in Tel Aviv.
TAU point guard Igor Rakocevic is still sidelined with a muscle tear in his left leg, but Zoran Planinic is hoping to pick up some of the slack after missing the first two Top 16 matches with a hand injury.
Maccabi Elite are at full strength for the encounter, but whatever the outcome both clubs are still favoured to go through to the quarter-finals in Group D.
Follow LIVE coverage of all of the night's Euroleague action starting with Partizan Belgrade v Olympiacos from 18:45 CET.