It was Italy versus Spain in front of the biggest-ever Mugello crowd for a MotoGP Sunday of 91,000 fans.
Pole-sitter Andrea Iannone made a flying start but it was Andrea Dovizioso who led into the first corner ahead of Lorenzo, who almost immediately took the initiative away from the Ducatis to lead at the end of the opening lap.
Another quick starter was Marc Marquez as the World Champion, starting P13, was up to sixth after the first corner, fourth at the end of lap one, and third as he took Iannone through the first corner on lap 2. A lap later he was up to second, pulling the move at the same corner on the other Ducati before hunting for Lorenzo.
But rather than catch the Yamaha rider, Marquez became embroiled in a fierce battle with the Ducatis who, like Lorenzo, were running the medium rear Bridgestone while Marquez was on the hard option. The trio traded blows before it became a four-way fight as Dani Pedrosa got involved. And all the while Lorenzo raced away into the distance.
The Spaniard was five seconds up the road when, after 10 laps, his team-mate Valentino Rossi's recovery from a tardy start – in which he dropped from P8 to P11 – finally began to pay dividends as he closed up on the battle for second. Two laps later he was firmly in the thick of things as he took fifth off Dovizioso, who later pulled into the pits with a rear chatter issue.
As Lorenzo continued to eke out an ever-growing advantage, Iannone, Marquez, Pedrosa and Rossi fought it out for the final two podium positions. But with six laps to go it was down to a three-way battle as Marquez crashed. The Honda rider lost the front end of his RC213V and slid off into the gravel. His crash gave Iannone a bit of breathing room while Rossi heaped more hurt on Honda as he took third off Pedrosa.
Lorenzo continued with his own personal race to the chequered flag, taking it by a comfortable 5.5s ahead of Iannone. Rossi completed the podium at his home race and held onto the lead in the riders' championship.
Pedrosa was fourth ahead of Bradley Smith and his Yamaha Tech 3 team-mate Pol Espargaro. Mavrick Vinales was seventh, a career-best MotoGP finish for the Spaniard.
Aleix Espargaro, Jack Miller and Nicky Hayden were early crashers while Stefan Bradl joined them on the sidelines. Alex De Angelis retired with a technical failure. Cal Crutchlow was the final rider out as he crashed out of sixth place with two laps to go.
1 Jorge LORENZO Movistar Yamaha MotoGP 41'39.173
2 Andrea IANNONE Ducati Team 5.563
3 Valentino ROSSI Movistar Yamaha MotoGP 6.661
4 Dani PEDROSA Repsol Honda Team 9.978
5 Bradley SMITH Monster Yamaha Tech 3 15.284
6 Pol ESPARGARO Monster Yamaha Tech 3 15.665
7 Maverick VIÑALES Team SUZUKI ECSTAR 23.805
8 Michele PIRRO Ducati Team 29.152
9 Danilo PETRUCCI Octo Pramac Racing 32.008
10 Yonny HERNANDEZ Octo Pramac Racing 34.571
11 Scott REDDING EG 0,0 Marc VDS 38.553
12 Loris BAZ Athinà Forward Racing 42.158
13 Hector BARBERA Avintia Racing 44.801
14 Alvaro BAUTISTA Aprilia Racing Team Gresini 50.435
15 Eugene LAVERTY Aspar MotoGP Team 53.060
16 Mike DI MEGLIO Avintia Racing 1'15.265
17 Karel ABRAHAM AB Motoracing 1'15.381
18 Marco MELANDRI Aprilia Racing Team Gresini 1'41.840
Cal CRUTCHLOW CWM LCR Honda 3 Laps
Marc MARQUEZ Repsol Honda Team 6 Laps
Andrea DOVIZIOSO Ducati Team 10 Laps
Stefan BRADL Athinà Forward Racing 20 Laps
Nicky HAYDEN Aspar MotoGP Team 20 Laps
Aleix ESPARGARO Team SUZUKI ECSTAR 21 Laps
Jack MILLER CWM LCR Honda 21 Laps
Alex DE ANGELIS E-Motion IodaRacing Team 21 Laps