Melandri followed in second, giving his beleaguered title hopes a significant boost on his home circuit, while Guintoli has seen his championship advantage whittled down to 13 points by his Aprilia team-mate.
A race of attrition, Chaz Davies ran with the leaders early on, but a mistake into the first turn on lap five would drop him back to eighth. The Welshman would battle his way back into fifth, only to low-side out of the race at the Roggia chicane on lap 12.
There was similar disappointment for Jonathan Rea, who suffered mechanical problems on his Pata Honda just five laps into the race.
In the end, Michel Fabrizio and Davide Giugliano would finish fifth and sixth, despite both enduring off-track excursions, with Leon Camier come home in seventh position aboard the sole remaining Fixi Crescent Suzuki, his team-mate Jules Cluzel having crashed on lap two.
Starting from the pit lane after failing to get away on the warm-up lap, Loris Baz recovered to a solid eighth place, while Ayrton Badovini won the battle of the Ducati riders by finishing ninth ahead of Max Neukirchner.
Just 13 riders would reach the finish line, with Fabrizio Lai, Vittorio Iannuzzo and Federico Sandi picking up the remaining available digits in 11th, 12th and 13th.