Former champions Chelsea will face Malmo in the last 32 of the Europa League while Arsenal will lock horns again with BATE Borisov.
The two sides met in the Europa League last season, the Gunners hammering the Belarussian side 6-0 at the Emirates.
Five-time champions Sevilla, currently second in La Liga, face a difficult tie against Lazio, beaten finalists in this competition in 1998, who are fifth in Serie A.
The 2004 champions Valencia will have to overcome Scottish champions Celtic while another Spanish side Villarreal, currently hovering just above the Liga relegation zone, face an Iberian battle when they take on Sporting.
Napoli, demoted to the Europa League after they were knocked out of the Champions League at the group stage, face Zurich.
Portuguese giants Benfica, three times runners-up, tackle Turkish side Galatasaray, Uefa Cup winners in 2000, and Inter Milan, another team who failed to progress to the Champions League knockout stage, will play Rapid Vienna.
The ties will take place on 12-14 and 20-21 February.
THE DRAW
Rennes v Betis
BATE Borisov v Arsenal
Malmo v Chelsea
Viktoria Plzen v Dinamo Zagreb
Club Brugge v Salzburg
Rapid Vienna v Inter Milan
Slavia Prague v Genk
Krasnodar v Bayer Leverkusen
Zurich v Napoli
Shakhtar Donetsk v Eintracht Frankfurt
Celtic v Valencia
Olympiakos v Dynamo Kiev
Lazio v Sevilla
Fenerbahce v Zenit Saint Petersburg
Sporting Lisbon v Villarreal
Galatasaray v Benfica