Manchester United head for the uneven Olimp-2 stadium surface to take on Rostov on Thursday and keep alive hopes of becoming one of the few teams to have won all three European cups.
United fans have been told not to wear their team's red colours in the Russian city to avoid re-igniting hooligan violence and Rostov coach Ivan Daniliants promised a "classy performance" against the illustrious English side.
United won the European Cup in 1968, the Cup Winners' Cup in 1991 and Champions League in 1999 and 2008. But they have never won the Europa League nor the old UEFA Cup.
If successful this year, United would join Juventus, Ajax, Bayern Munich and Chelsea, who have already lifted all three European club trophies.
Having won their first trophy under Jose Mourinho with a 3-2 win over Southampton in the League Cup final, United need a strong performance in the first leg in Rostov to open the road to the quarter-finals.
That would take them into the draw with the winners from key ties such as Lyon v Roma, the all-German Schalke v Borussia Monchengladbach, Copenhagen v Ajax and Olympiakos v Besiktas.
Mourinho never lost in Russia with his previous clubs (Chelsea, Inter Milan and Real Madrid), but he is not happy going to Rostov, last season's Russian league runners-up, to play on the bumpy pitch.
"It's a bad draw in every aspect. It's far and it's difficult," Mourinho told Man United official site.
"It's far and comes in a very bad period for us, difficult because they're a very difficult team."
United won their first trophy under Mourinho when they took the English League Cup final 3-2 against Southampton. But Mourinho admitted they were lucky and at the weekend saw his side held 1-1 by unfancied Bournemouth.
United are far from the Champions League qualifying places and Mourinho has expressed his disappointment at United's low scoring rate.
"We need to score goals – other teams with less chances score goals," Mourinho told his club's official site.
"Against Southampton in the League Cup final, we had five chances and scored three but, against Bournemouth with more than 10 chances, we scored one goal."
On Thursday the Reds will be without Eric Bailly, who was sent off in their round of 32 1-0 win at Saint-Etienne.
United midfielder Juan Mata said it would be "a long trip that is going to test the strength of the team in every sense. The Russian side is particularly strong at home: this season they have defeated Bayern Munich and Ajax, for instance. That gives you an idea of how tough they are."
Mourinho left Rooney and leftback Luke Shaw at home along with Bastian Schweinsteiger. Armenian forward Henrikh Mkhitaryan returns to the 20-man squad after recovering from an injury incurred just after scoring the St Etienne winner.
Rostov sent a clear warning to the Red Devils when they routed Tomsk 6-0 on Friday.
Rostov showed no signs of rustiness in their first domestic match after the long winter break.
But head coach Daniliants said he and his men realised that Manchester United will be a completely different story.
"Man United are a top-class team and to oppose them is an honourable and a pleasant task," he told the press.
"It demands full mobilisation and colossal responsibility. Hopefully, we will come into this match on top, both physically and mentally. The match is sold out and we're set to give our fans a classy performance."
Rostov will likely be at full-strength except for doubts over injured first-choice goalkeeper Soslan Dzhanayev.
Europa League last 16 fixtures
Celta Vigo (ESP) v Krasnodar (RUS)
Apoel Nicosia (CYP) v Anderlecht (BEL)
Schalke 04 (GER) v Borussia Mönchengladbach (GER)
Lyon (FRA) v Roma (ITA)
Rostov (RUS) v Manchester United (ENG)
Olympiakos (GRE) v Besiktas (TUR)
Gent (BEL) v Genk (BEL)
FC Copenhagen (DEN) v Ajax (NED)
1st leg, March 9; 2nd leg, March 16