Athletic Bilbao will take a two-goal buffer into the second leg of their Copa del Rey last 32 match against Linense, but fellow La Liga sides Eibar, Malaga, Villarreal and Real Sociedad will need to come from behind.
Basque side Bilbao, who are the second-most successful team in the tournament behind Barcelona having won it 23 times, were always in charge at the Municipal La Línea as they beat their hosts 2-0.
Manager Ernesto Valverde decided to rest leading marksman Aritz Aduriz, but striker Kike Sola put the visitors in the ascendency very early on with a goal after 13 minutes.
And they were in complete control six minutes later when midfielder Ander Iturraspe crossed from a free-kick with defender Aymeric Laporte heading home from close range.
Fellow Basque side Eibar have it all to do in the second leg after they went down 3-0 against Segunda Division side Ponferradina at El Toralin with the goals coming from Luka Djordjevic and William Jebor.
Djordjevic, who is on loan from Zenit St Petersburg, gave the hosts the lead after 11 minutes and fellow forward Jebor doubled their advantage 15 minutes later following a cross from Ukrainian midfielder Dmytro Khomchenovsky.
Although Eibar dominated possession, it was Ponferradina who had more shots on target and they put one foot in the next round when Khomchenovsky smashed home a third goal in the 53rd minute.
It is all square in the all-La Liga clash between Levante and Espanyol after Mamadou Sylla's goal for the visitors was cancelled out by a late strike from Roger Marti.
The Catalan side fashioned the better chances, but they had to wait until the 68th minute to get on the scoresheet with striker Sylla getting the breakthrough, but Roger equalised in the 83rd minute.
Meanwhile at El Alcoraz, Villarreal twice come from behind but still lost 3-2 against Segunda Division side Huesca.
Striker Luis Fernandez scored from a set piece after just three minutes and it took the visitors until the second half to find their first equaliser with Matias Nahuel hitting a long-range effort.
However, two minutes later and defender Mateo Musacchio gave away a penalty after he fouled Tyronne in the box.
Former Arsenal and Atletico Madrid player Fran Merida, who started his career with Barcelona, stepped up to convert from the spot, but Villarreal again hit back with striker Cedric Bakambu finding the left corner after being set through by Manu Trigueros.
Darwin Machis gave Huesca the lead for a third time when his right-footed shot found the top right corner and this time there was no comeback from Villarreal.
Malaga will also need to overcome a deficit after they were beaten 2-1 by second-tier side Mirandes at Anduva.
Striker Alex Garcia gave the hosts the lead in the 34th minute from a corner, but Paraguayan international Roque Santa Cruz levelled things up seven minutes into the second half.
However, substitute striker Lago Junior gave Mirandes a slender lead for the second leg after scoring from a Marco Sangalli cross.
In an all-La Liga clash in the night's final game, Las Palmas downed Real Sociedad 2-1 at the Estadio de Gran Canaria.
It was Sociedad who took the lead in just the 11th minute, with Mikel Oyarzabal the beneficiary of some poor passing from the home defence. The Spaniard's shot was blocked, but Bruma was on hand to put away the rebound.
Las Palmas levelled matters on the half hour mark, when Asdrúbal was brought down in the area by Diego Reyes. However, the striker's penalty was saved by Oier, but the Sociedad keeper could do nothing to stop the 24-year-old's follow-up attempt.
Raul Lizoain in the Las Palmas goal was also forced to save an attempt from 12 yards in the 43rd minute, when Ruben Pardo couldn't capitalise after Javier Garrido had brought down Gonzalo Castro.
It was the home side that would find the winner though, with Hernan on hand to header home Nabil El Zhar's cross.
Sociedad had their chances to draw level, but it's Las Palmas who head into the second leg with the advantage.