Twice European Cup winners Manchester United, whose attack boasts Wayne Rooney and Ruud van Nistelrooy, must end a surprising three-match scoring drought to avoid Champions League elimination in Lisbon on Wednesday.
Benfica, who a United side inspired by George Best memorably crushed 5-1 in Portugal in 1966 and beat at Wembley to lift the trophy for the first time two years later, stand between them and a place in the knockout phase for the 10th successive season.
United have not scored in Group D since beating Benfica 2-1 at Old Trafford in September and are in a precarious third place a point behind leaders Villarreal. They are level with Lille but have an inferior head-to-head record against the French team.
Benfica are bottom a point further back but will qualify from the tightest of the eight groups with a victory.
United could go through with a draw but that would only happen if Villarreal beat Lille at home in the other game.
The only other berth in the knockout phase still undecided is the runner-up in Group C, which has already been won by tournament favourites Barcelona.
Udinese will secure second place with a draw at home to European Footballer of the Year Ronaldinho's team but defeat for the Italians would open the way for Werder Bremen if they beat Panathinaikos at home.
In Group A, Bayern Munich and Juventus will be vying for first place when they face Rapid Vienna and Club Bruges away respectively.
Arsenal, who have won Group B with a perfect 15 points so far, and second-placed Ajax meet at Highbury with their berths secured, while Swiss surprise package Thun need a draw at Sparta Prague to clinch a UEFA Cup qualifying spot in third place.
Fixtures in Groups E to H were completed on Tuesday with 2005 finalists AC Milan, PSV Eindhoven and Rangers joining holders Liverpool, Chelsea, Inter Milan, Olympique Lyon and Real Madrid in the knockout phase.
