FC Nordsjaelland, who made last season's Champions League group stages, were dumped out by Swedish champions Elfsborg.
After a 1-1 draw in Sweden, Nordsjaelland would have been favourites to progress but a single goal from their former striker Mikkel Beckmann gave their opponents a 1-0 win, which was enough to take them through.
Another shock saw Bundesliga outfit Stuttgart go out to Croatian side Rijeka, after a 2-2 draw in Germany meant they go out 4-3 on aggregate. Rijeka went through after a last-minute goal from Goran Mujanovic.
Serbian champions Partizan Belgrade also went out despite taking a 1-0 advantage into their second-leg with FC Thun - they were hammered 3-0 in Switzerland.
Italians Udinese could not overhaul a 3-1 first leg deficit to Slovan Liberec, as they could only claim a 1-1 draw in the Czech Republic.
Fiorentina did manage to make it through, but only just on away goals after losing 1-0 at home to Grasshoppers.
St Etienne bowed out as they lost 5-3 on aggregate after losing 1-0 at home to Danish outfit Esbjerg with the only goal coming from Mustapha Bayal Sall - who put through his own net with 17 minutes left.
2006 and 2007 champions Sevilla strolled into the next round with a 9-1 aggregate win over Slask Wroclaw after a 5-0 second leg triumph in Poland.
Sevilla's city rivals Real Betis had an equally comfortable time, as they won 6-0 against Jablonec giving them an 8-1 aggregate win.
Dynamo Kiev eased into the group stages with a comfortable 5-1 win over Kazak outfit Aktobe in the Ukrainian capital.
Likewise Rubin Kazan made light work of their tie with Molde, claiming a 5-0 aggregate success after a 3-0 win in Russia.
There was a shock elsewhere in Russia, however, as Spartak Moscow bowed out at the hands of Swiss side St Gallen. After a 1-1 draw in Switzerland, a 4-2 win for the visitors including two goals from Goran Karanovic - gave the visitors the shock win.
Two time winners Feyenoord went out to Russian side Kuban Krasnodar after going down 2-1 in Rotterdam, going out 3-1 on aggregate.
Zulte-Waregem progressed after a 2-1 win in Cyprus over APOEL Nicosia, which gave them a 3-2 aggregate success - but there was success for one Cypriot side as Apollon went through as Nice could only win 1-0 in France, meaning they go out 2-1 overall.
Moldovan champions FC Sheriff progressed after a 2-1 win over Vojvodina, whilst Turkish giants Besiktas also booked their place in the next round as they won 2-0 in Istanbul against Tromso.
Eintracht Frankfurt, Dnipro, Maccabi Haifa, Rapid Vienna, Trabzonspor, Genk, Standard Liege, Salzburg and Estoril all eased into the group stages after comfortable aggregate wins.
AZ Alkmaar secured their place in the group stage on the away-goals rule, despite Atromitos completing a 2-0 second-leg win on the resumption of an abandoned tie.
The Greek club were leading 1-0 at the AFAS Stadion on Thursday night - but trailing 3-2 on aggregate - when a small fire broke out on the roof of the stadium, forcing the abandonment of the match shortly before the hour mark.
When play resumed on Friday morning, Thanasis Karagounis soon made it 3-3 on aggregate with a goal in the 74th minute, but AZ's earlier 3-1 success in Athens saw the 2009 Eredivisie champions through to the group stage on away goals.
Thursday's match had seen AZ reduced to 10 men after only two minutes when Markus Henriksen was sent off.
Dimitrios Papadopoulos, having missed a first-half penalty, put the visitors in front in the 53rd minute, but the match was called off shortly after.