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Franchitti, who also won the fabled race in 2007 and 2010, was followed across the finish line under a caution flag by Chip Ganassi Racing team-mate Scott Dixon of New Zealand and Brazil's Tony Kanaan.
"What a race. I think Dan Wheldon would be proud of this one," Franchitti said, dedicating the triumph to the 2011 winner from England who was killed in a crash last October at Las Vegas.
Franchitti, who fell behind early after his car was struck on pit row, seized the lead from Kanaan on a restart with six laps to go in the 200-lap showdown around the 2.5 mile (4km) Indianapolis Motor Speedway oval.
After Franchitti and Dixon traded the lead over the next few laps, Sato moved past Dixon into second behind the Scotsman with two laps remaining and made his run at the lead in the first turn of the last lap.
Sato, trying to become the first Japanese driver to win an IndyCar race, went low on the inside of the track and side-by-side with Franchitti, but lost control and spun into the outer wall as Franchitti sped away for the victory.
"I moved over and saw he was coming," Franchitti said. "I came back over and he got loose underneath me. I moved over to give him room and just managed to keep it going."
Sato, who was not injured, settled for 17th and complained that Franchitti did not allow him enough room to make the turn on the final lap.
"I was going for the win," Sato said. "Very last lap, good tow from Dario. I saw a good opportunity to the inside. It looks like he didn't give me enough room to go there. I was below the white line.
"I was already in (position). He didn't move up. Kept on pushing. I had nowhere to go. It's a little disappointing."
Dixon was undone by the crash, which froze the racers in their positions and denied him a chance to make a move for the pass at the end.
"I'm super gutted," Dixon said. "It's tough when you get so close to have it ripped away from you. So close. We definitely had the car.
"I wasn't expecting Sato to dive in there with two to go. He was pretty aggressive all day. I thought we were in good position to get a run at both of them on the last lap. They touched. All credit to Dario to save it."
Wheldon was in the thoughts of Kanaan, who along with Franchitti and Dixon were Wheldon's best friends in the series.
"His best friends fighting for the win, I knew the odds were one of us would do it," Kanaan said. "To lose this one like this was an honour. Danny, wherever he is right now, is extremely happy, his three best friends in the top three."
New IndyCar engines and chassis being raced at Indy for the first time were tested by near-record heat. Racers had smashed the old record for Indy 500 lead changes, 29 in 1960, with 22 laps remaining, well ahead of the closing drama.
While Chevrolet-powered teams dominated qualifying, taking nine of the 10 top spots, Franchitti and Dixon used Honda motors.
Franchitti suffered an early setback that dropped him to 30th. Venezuelan E.J. Viso's car struck the rear of Franchitti's as both were approaching their pits for the day's first stop, forcing an extended stay for the Scotsman.
"Viso, what a clown," Franchitti said over his radio.
But Franchitti, who started 16th, worked his way through the field to be in the lead after passing Sato with 48 laps remaining. Franchitti and Dixon exchanged the lead from there through pit stops, setting up the final lap.
"It was a great to come back after being hit in the pit lane and spun," Franchitti said.
Spain's Oriol Servia was fourth, followed in order by Aussie pole-sitter Ryan Briscoe, Canada's James Hinchcliffe and England's Justin Wilson.
England's Mike Conway crashed in the first turn on lap 81, his car going airborne and also taking out the car of Aussie Will Power. Conway had damaged his car's front wing by knocking over his pit crew's fuel man in pit lane.
That led to the wreck that ended the day for Power, the IndyCar season points leader who entered the 500 on a three-race win streak. No one was injured in the mishaps.
Swiss driver Simona de Silvestro and Frenchman Jean Alesi, a former F1 racer and the oldest starter making his Indy debut at age 47, were black-flagged early as their Lotus-powered cars could not sustain competitive speed.
"I give my heart, my passion to be here," Alesi said. "We're disappointed with the engine performance."
Results from Sunday's 96th Indianapolis 500, a 200-lap IndyCar race over the 2.5-mile (4km) Indianapolis Motor Speedway oval with driver, car, laps and reason out if any:
1. Dario Franchitti (SCO), Dallara-Honda, 200 laps in 2 hours 58 minutes 51.2532 seconds at 268.374 km/h
2. Scott Dixon (NZL), Dallara-Honda under caution on same lap
3. Tony Kanaan (BRA), Dallara-Chevy, same lap
4. Oriol Servia (ESP), Dallara-Chevy, s.l.
5. Ryan Briscoe (AUS), Dallara-Chevy, s.l.
6. James Hinchcliffe (CAN), Dallara-Chevy, s.l.
7. Justin Wilson (ENG), Dallara-Honda, s.l.
8. Charlie Kimball (USA), Dallara-Honda, s.l.
9. Townsend Bell (USA), Dallara-Honda, s.l.
10. Helio Castroneves (BRA), Dallara-Chevy, s.l.
11. Rubens Barrichello (BRA), Dallara-Chevy, s.l.
12. Alex Tagliani (CAN), Dallara-Honda, s.l.
13. Graham Rahal (USA), Dallara-Honda, s.l.
14. J.R. Hildebrand (USA), Dallara-Chevy, s.l.
15. James Jakes (ENG), Dallara-Honda, s.l.
16. Simon Pagenaud (FRA), Dallara-Honda, s.l.
17. Takuma Sato (JPN), Dallara-Honda, one lap down, crash
18. E.J. Viso (VEN), Dallara-Chevy, s.l.
19. Michel Jourdain (MEX), Dallara-Honda, s.l.
20. Sebastien Bourdais (FRA), Dallara-Chevy, s.l.
21. Ed Carpenter (USA), Dallara-Chevy, s.l.
22. Katherine Legge (ENG), Dallara-Chevy, s.l.
23. Ana Beatriz (BRA), Dallara-Chevy, 10 laps down
24. Marco Andretti (USA), Dallara-Chevy, 13 laps down, crash
25. Josef Newgarden (USA), Dallara-Honda, 39 laps down, mechanical
26. Sebastian Saavedra (COL), Dallara-Chevy, 57 laps down, electrical
27. Ryan Hunter-Reay (USA), Dallara-Chevy, 77 laps down, suspension
28. Will Power (AUS), Dallara-Chevy, 121 laps down, crash
29. Mike Conway (ENG), Dallara-Honda, 122 laps down, crash
30. Bryan Clauson (USA), Dallara-Honda, 154 laps down, mechanical
31. Wade Cunningham (NZL), Dallara-Honda, 158 laps down, electrical
32. Simona de Silvestro (SUI), Dallara-Lotus, 190 laps down, handling
33. Jean Alesi (FRA), Dallara-Lotus, 191 laps down, handling
