Sevilla - who have won the competition a record five times - have been drawn against Romanian side Cluj, who came through a group which included Lazio and Rennes.
Getafe, who have previously reached the quarter-finals of the competition, have been paired with Dutch champions Ajax - who reached the semi-finals of the Champions League last season, and have previously faced Valencia in that competition this campaign.
Espanyol - who are in the competition for the first time since losing the 2007 showpiece - are up against Premier League side Wolverhampton Wanderers.