Santi Mina (twice), Daniel Parejo, Alvaro Negredo, Andre Gomes and Rodrigo scored for Valencia at Mestalla Stadium.
Meanwhile Danish team Midtjylland beat England's Manchester United 2-1 in Denmark.
Manchester United scored the first goal thanks to Memphis Depay. But Midtjylland's Pione Sisto and Nigerian striker Paul Onuachu scored the next two for the win.
The return matches will be played on Feb. 24 and 25.
Thursday's results:
Anderlecht 1-0 Olympiacos
Midtjylland 2-1 Manchester United
Fiorentina 1-1 Tottenham
Borussia Dortmund 2-0 Porto
Villarreal 1-0 Napoli
Saint-Etienne 3-2 Basel
Sevilla 3-0 Molde
Sporting Lisbon 0-1 Bayer Leverkusen
Valencia 6-0 Rapid Wien
Augsburg 0-0 Liverpool
Sparta Prague 1-0 Krasnodar
Galatasaray 1-1 Lazio
Sion 1-2 Braga
Shakhtar Donetsk 0-0 Schalke 04
Olympique Marseille 0-1 Athletic Bilbao
