Spanish Primera Liga frontrunners Villarreal and Sevilla suffered shock defeats at third-tier sides Poli Ejido and Ponferradina in the first legs of their King's Cup last-32 ties on Wednesday.
Villarreal were humbled 5-0 by Poli Ejido, with Jorge Molina scoring a hat-trick and Gregory a brace for the south coast club, while Sevilla lost 1-0 to Ponferradina thanks to a 90th-minute strike from Cristian Portilla.
Earlier, Fernando Morientes netted twice as holders Valencia brushed aside modest Portugalete 4-1.
The lowest-ranked team left in the competition, fourth-tier Portugalete held out for just 11 minutes before Morientes lifted a cross from Hugo Viana over the goalkeeper and into the net.
Midfielder Vicente doubled the visitors' advantage 10 minutes later, driving home a crisp left-foot shot.
Urko Vera pulled back a goal for the Basque club just after the break with a powerful header that squirmed under goalkeeper Guaita into the Valencia net before Viana set up Morientes for Valencia's third shortly afterwards.
Valencia poured forward as the Portugalete players tired and Nicola Zigic swept in Valencia's fourth goal shortly before the end after he was picked out by Pablo Hernandez.
Valencia, who left joint Primera Liga top scorer David Villa out of Wednesday's squad, beat Getafe 3-1 in last season's final to claim their seventh King's Cup.
There were four all-Primera Liga ties on Wednesday. Getafe, runners-up over the last two years, played out a dull 0-0 draw at home to Osasuna and Athletic Bilbao beat visiting Recreativo Huelva 2-0.
Numancia lost 1-0 at home to Sporting Gijon and Malaga and Real Mallorca drew 1-1 in Malaga.
Espanyol were held 2-2 at second-division Celta Vigo while Atletico Madrid won 1-0 at third-tier Orihuela thanks to a goal from striker Diego Forlan just before the break.
The arrival of the top-flight clubs in the tournament sees third-tier Real Union play league champions and 17-times winners Real Madrid on Thursday in the final first-leg tie of the round.
In Tuesday's only match, teenage striker Bojan Krkic gave an under-strength Barcelona a 1-0 win at Segunda B (third-tier) side Benidorm.
Return matches are scheduled for November 12.