The Frenchman won by 1.352 seconds from Irishman Eugene Laverty, his team-mate at the factory team, with Red Devils Roma rider Michel Fabrizio only seven-thousandths of a second further back.
It is the second time that the Noale manufacturer has taken all three podium spots, the other occasion being at the Nurburgring last year, while it is Guintoli's fourth win in WSBK as he gets to grips with the RSV4.
Pole sitter Carlos Checa crashed out on lap 13 after hitting Marco Melandri (BMW Motorrad GoldBet) with his Ducati Alstare at turn four, with the Italian also forced to retire - he had overtaken the Spaniard moments beforehand.
Laverty took the lead off the line from second, with Tom Sykes, Checa, Melandri and Leon Haslam following ahead of Guintoli.
Checa, Haslam and Melandri swapped position several times while Laverty built a lead.
Guintoli worked his way through the trio by lap 10. Checa then crashed into Melandri, with the latter unhurt and former taken to hospital after being briefly knocked unconscious. He will not start race two.
Guintoli ate up the gap to Laverty and passed him on lap 15 - he would not be caught - while the Irishman fought off Fabrizio, who had surged up the field after dropping to 11th from third at the start.
Chaz Davies was fourth ahead of Sykes, Loris Baz and British trio Leon Haslam, Jonathan Rea and Leon Camier.
1. Sylvain Guintoli FRA Aprilia 33:47.109
2. Eugene Laverty IRL Aprilia +1.352s
3. Michel Fabrizio ITA Red Devils Roma Aprilia +1.359s
4. Chaz Davies GBR BMW GoldBet +5.702s
5. Tom Sykes GBR Kawasaki +5.753s
6. Loris Baz FRA Kawasaki +6.769s
7. Leon Haslam GBR Pata Honda +6.830s
8. Jonathan Rea GBR Pata Honda +17.944s
9. Leon Camier GBR Fixi Crescent Suzuki +19.152s
10. Max Neukirchner GER MR Ducati +26.557s
11. Jules Cluzel FRA Fixi Crescent Suzuki +30.305s
12. Ivan Clementi ITA HTM Racing BMW +30.411s
13. Alexander Lundh SWE Pedercini Kawasaki +45.185s
14. Glenn Allerton AUS Next Gen BMW +48.632s
15. Jamie Stauffer AUS Honda +53.453s
16. Federico Sandi ITA Pedercini Kawasaki +1m 22.730s
17. Vittorio Iannuzzo ITA Grillini Dentalmatic BMW +4 laps
18. Carlos Checa ESP Alstare Ducati (12 laps)
19. Marco Melandri ITA BMW GoldBet (12 laps)
20. Davide Giugliano ITA Althea Racing (2 laps)