Cipollini, of the Acqua e Sapone team, was winning the event for the third time overall but it comes nine years after his last Ghent-Wevelgem triumph in 1993. He also won the event in 1992.
The 35-year-old is enjoying something of an Indian summer in a career which began way back in 1989.
He won the opening World Cup event of this season with a first career victory in the Milan-San Remo classic.
After 207km of racing here Wednesday, the sprint specialist known affectionately as the "Lion King" showed he still has juice in the legs as he held off American duo Fred Rodriguez and George Hincapie in the race for the line.
Rodriguez took second place while last year's winner Hincapie a US Postal teammate of Tour de France champion Lance Armstrong came third after they had pulled ahead of Belgium's Hendrik Van Dyck and Slovenian Martin Hvastija.
But while Cipollini is known for his sprinting prowess, the flashy Italian veteran was keen to promote his other race qualities.
"I showed that it's not just sprinting I'm good at," said Cipollini as he highlighted his early efforts to join the race contenders.
"At the front there were some good riders like Hincapie and Hvastija that's why I went with them. Otherwise the race would have been finished for me."
The decisive breakaway came just after the second ascent of the Kemmel climb with 35 kilometres to race, with Cipollini closing a 10-second gap on the lead group to stake his place among Hincapie and Co.
The five riders maintained their lead over the peloton and in the dying kilometers toyed with each other as they fought the cross winds in a bid to get the best position for the upcoming sprint.
In the last kilometre neither Rodriguez or Hincapie was able to shake off Cipollini, who veered off to the right and powered ahead in the dying meters before raising his arms in victory prior to the line to highlight the ease of his victory.
The pursuing peloton arrived around 1 minute 30 seconds behind.
Cipollini, who is the current World Cup leader, said he would not take part in this season's highlight of the one-day classic season the mud-encrusted Paris-Roubaix.
"It's a pity but it's just not possible to do everything," admitted the Tuscan, who has won 12 stages in the Tour de France but has never finished the world's most grueling bike race.
Results of Gent-Wevelgem (208km), top 20:
1. Mario Cipollini (Ita) Acqua e Sapone 4hrs 39mon 00sec
2. Fred Rodriguez (USA) same time
3. George Hincapie (USA) s.t.
4. Hendrik Van Dyck (Bel) s.t.
5. Martin Hvastija (Slo) at 10sec
6. Robert Hunter (Rsa) 1min 29sec
7. Tom Boonen (Bel) 1:29
8. Erik Zabel (Ger) 1:29
9. Tristan Hoffman (Ned) 1:29
10. Johan Museeuw (Bel) 1:29
11. Servais Knaven (Ned) 1:29
12. Aart Vierhouten (Ned) 1:29
13. Hans De Clercq (Bel) 1:29
14. Franck Pencole (Fra) 1:29
15. Paul Van Hyfte (Bel) 1:29
16. Andreas Klier (Ger) 1:43
17. Marco Serpellini (Ita) 2:18
18. Matthias Buxhofer (Aut) 2:21
19. Remco Van der Ven (Ned) 4:19
20. Danilo Hondo (Ger) 4:19