The Androni Giocattoli rider attacked as the final 13.5km lap began and pulled out a huge margin to win by 27 seconds from Danilo Di Luca (Acqua & Sapone), one of three riders to try and go with Pellizotti.
Liquigas-Cannondale's Moreno Moser and Katusha's Giampaolo Carusa finished third and fourth, with the rest of the field headed by Moser's team-mate Vincenzo Nibali over two minutes behind the winner on a brutal course which saw only a handful of riders finishing the 255km race.
"Anyone who knows me will know how hard I tried in that last kilometre,” Pellizotti said. "At 400 metres to go, I knew I’d won and was able to enjoy it. I wish that it could have never ended.
“I must thank Androni for the great trust they have shown in me. After they confirmed my appointment I was able to train in the best possible way for this race.”
Michele Scarponi had an advantage of almost 90 seconds with two laps of the course and 27km remaining, but as the race hurtled towards its conclusion his lead was quickly worn down.
He was eventually swallowed up by the three podium men, with Nibali and Caruso just ahead at the beginning of the final lap before Pellizotti attacked as the final climb began.
Caruso stayed with the eventual winner for a few kilometres, but the fresher Pellizotti piled on the pressure to pull clear and 31-year-old Caruso was hauled in by Di Luca and Moser.
1. Franco Pellizotti (Ita) Androni Giocattoli-Venezuela 6:43:12
2. Danilo Di Luca (Ita) Acqua & Sapone 0:00:27
3. Moreno Moser (Ita) Liquigas-Cannondale "
4. Giampaolo Caruso (Ita) Katusha Team "
5. Vincenzo Nibali (Ita) Liquigas-Cannondale 0:02:11
6. Michele Scarponi (Ita) Lampre - ISD 0:02:13
7. Simone Ponzi (Ita) Astana Pro Team 0:02:03
8. Daniele Ratto (Ita) Liquigas-Cannondale 0:03:11
9. Francesco Gavazzi (Ita) Astana Pro Team "
10. Matteo Rabottini (Ita) Farnese Vini - Selle Italia "
11. Ivan Santaromita (Ita) BMC Racing Team "
12. Francesco Failli (Ita) Farnese Vini - Selle Italia "
13. Manuele Mori (Ita) Lampre - ISD "
14. Domenico Pozzovivo (Ita) Colnago - CSF Inox 0:03:13
15. Davide Rebellin (Ita) Meridiana Kamen Team 0:03:15
16. Leonardo Bertagnolli (Ita) Lampre - ISD 0:03:35