Napoli's unbeaten start to the season and 11-match winning streak in Serie A ended on Wednesday when Edin Dzeko's second-half goal secured Inter Milan a 1-0 victory.
While Napoli dominated possession in the goalless first half, Inter striker Dzeko broke the deadlock in the 56th minute when he headed in a cross from Federico DiMarco.
- Stream on ESPN+: LaLiga, Bundesliga, more (U.S.)
"Being the first to beat Napoli, who were the only side in Europe's top leagues without defeat this season, is a big confidence booster," Inter manager Simone Inzaghi said to DAZN.
"I am very proud of my team because they helped each other out on the field, they were a pleasure to watch and we put in a great performance for the fans."
Napoli top the table with 41 points after 16 games. They lead second-placed AC Milan by five points, while fourth-placed Inter are on 33 points.
"We can do more in terms of quality, some of our players were a little below par today," Napoli coach Luciano Spalletti said.
"You are meant to move the ball side to side to pull the opposition out of shape, but that doesn't work when you do it slowly and without the usual quality."
Inter went close after four minutes when Romelu Lukaku crossed into the box, but the angle was too narrow for DiMarco, who sent his effort wide.
Lukaku then shot over after 41 minutes after being played in by a backheel from Nicolo Barella.
Barella fed DiMarco in the box a minute later, but Napoli keeper Alex Meret saved his effort, before the offside flag was raised.
The visitors started to build momentum after Dzeko's goal but struggled to create opportunities.
"Games have different moments, towards the end of the first half, we went deeper and allowed Napoli more possession, but we could've scored three goals in the first half," Inzaghi said.
Napoli had their best chance on the 90-minute mark when Giacomo Raspadori managed to get a shot on goal from inside the box, but keeper Andre Onana made a reflex save.