Sebastian Fernandez scored the only goal of the game as Uruguay stunned Italy with a smash-and-grab 1-0 win at the Stadio Olimpico here on Tuesday.
In a game that had seven bookings and a red card for the visitors, Italy dominated for long spells but lacked the cutting edge their opponents found inside three mintues.
It was Italy coach Cesare Prandelli's third defeat in a friendly since taking over the role 18 months ago, although he has remained unbeaten in competitive fixtures and his team qualified easily for the European Championships next year.
Italy almost got off to a dream start in the opening minute but Mario Balotelli flicked his shot straight into Fernando Muslera's grasp from Pablo Osvaldo's through ball.
And the hosts paid for that two minutes later as former Juventus full-back Martin Caceres crossed from the right and Fernandez's bobbled finish found its way into the net despite the attentions of four ball-watching Italy defenders.
From then on Italy took total control, threatening most down the right.
Riccardo Montolivo and Balotelli both hit efforts from outside the box that were too close to Muslera.
Right-back Christian Maggio crossed for Osvaldo but his header, from a clearly offside position not spotted by the officials, went well wide.
Daniele De Rossi had a gilt-edged opportunity from close in but he failed to really catch his half-volley, which hit the first defender.
In a rare counter-attack Carceres just failed to get a touch on Cristian Rodriguez's free-kick six yards out and right in front of goal.
Osvaldo came closest for Italy but his header from an Andrea Pirlo corner went inches wide.
Another Maggio cross found Balotelli but after smart control and a quick turn his shot once again was too close to Muslera.
At the start of the second period Napoli hot-shot Edinson Cavani forced Italy goalkeeper Gianluigi Buffon into a low save with a header while Azzurri substitute Simone Pepe had a crisp near-post effort that Muslera got down.
Italy were creating most of the danger but both Maggio and Osvaldo shot wastefully high from good positions.
Azzurri substitute Alessandro Matri hit a volley wide while on the counter Cavani's blast hit his own player.
Italy's best spell came in the last quarter hour when Federico Balzaretti burst forward down the left, played a one-two with De Rossi but then scuffed his volleyed finish, allowing Muslera to push the ball behind for a corner.
From the dead-ball Giorgio Chiellini shot goalwards with the ball coming off Cavani and spinning agonisingly wide.
The Portuguese referee Duarte Gomes then unnecessarily sent-off Alvaro Pereira for a second booking, given for a handball the full-back could do nothing about.