Cadiz striker 'Choco' Lozano made history with his 16th minute goal to give the recently-promoted side their first-ever away win against Real Madrid and hand the reigning champions their first defeat of the La Liga season.
Cadiz, who have won all three of their away games this season, had already had four decent chances before Lozano's goal and were full value for their victory against a rival that rarely threatened, although Karim Benzema did hit the bar with a dipping shot eight minutes from time, reports Xinhua news agency.
Sergio Ramos was forced out of the game in the 45th minute after hurting his knee in a collision with Lozano and could now be a doubt for his side's Champions League debut against Shakhtar Donetsk and next Saturday's 'Clasico' away to FC Barcelona.
Meanwhile, Barca also crashed to a 0-1 defeat in Getafe with Jaime Mata's second-half penalty condemning Ronald Koeman to his first defeat as Barca coach.
Ousmane Dembele, along with new signings Pedri and Sergino Dest, all started for Barca, who controlled the first half and should have scored through Antoine Griezmann.
However, Mata converted his spot-kick which was awarded after a rash Frenkie de Jong challenge on Djene. Barca never looked like getting back into the game after that.
Djene headed against his own bar under pressure in injury-time, but Barca lacked the sharpness to break down their rivals.
Luis Suarez got back on the goal trail for Atletico Madrid as the Uruguayan opened the scoring in their 2-0 win away to Celta Vigo. Yannick Carrasco scored Atletico's second goal deep into injury-time.
Granada kept up their excellent start to the season as they ended Sevilla's unbeaten start to the campaign with a 1-0 win.