Sevilla crushed Slask Wroclaw of Poland 4-1 in an easy victory on home soil with Marko Marin on target twice. Ivan Rakitic and Kevin Gameiro also found the net.
Jorge Molina and Cedric fired the goals as Spanish club Real Betis beat Czech team Jablonec 2-1 - however, Betis had to graft until the 87th minute for their winner after Jan Kopic equalised for Jablonec.
Fiorentina resisted a fightback from Grasshoppers of Switzerland to prevail 2-1. Juan Cuadrado and Mario Gomez gave the Serie A club a 2-0 lead before Anat Ngamukol pulled one back for the hosts.
Senegal forward Ibrahima Balde struck in the 61st minute to give Kuban a 1-0 home triumph over Dutch giants Feyenoord.
Another Dutch club, AZ Alkmaar, fared better with a 3-1 win against Greece's Atromitos, Johann Gudmundsson finishing with two goals.
Big spending Rubin Kazan defeated Norwegian minnows Molde 2-0 with Venezuela's Jose Rondon scoring twice.
German midfielder Alexander Meier was another player to finish with a brace as Frankfurt swept aside Azerbaijan's Qarabag.
There was misery for Stuttgart as they went down 2-1 to Rijeka, Vedad Ibisevic's late strike at least giving them an away goal.
Apollon's Italian striker Gaston Sangoy fired the Cypriot club to a surprise 2-0 victory over Nice.
There were wins for Dynamo Kyiv, Maccabi Haifa, Standard Liege, Salzburg, Saint-Etienne, Dnipro Dnipropetrovsk, Trabzonspor, Genk, Tromso, Braga.
Chornomorets Odesa, Partizan, Slovan Liberec, Rapid Vienna and Estoril Praia were also victorious after the first leg.
Of the 30 games played - Maccabi Tel Aviv's clash with PAOK was cancelled - there were only four draws.
St Gallen's match against Spartak Moscow, Elfsborg's showdown with Nordsjaelland, Vojvodina against Sheriff and Zulte Waregem's clash with APOEL finished level.