Nicky then promptly set off like a rocket, while Rossi was soon past Bayliss for second - but further back Barros's hopes would last less than a lap when he appeared to be clipped by second in the championship Melandri at the final turn, felling both riders.
Meanwhile, by the end of lap one Hayden held a one-second lead over Rossi - and would relentlessly increase that advantage over the following laps as he attempted to disappear into the distance. The tactic worked until lap 5, when Rossi hit his own comfort zone and halted Hayden's lead at 1.7secs.
But while a respectful distance separated the top two, the fight for third between Bayliss, Biaggi and Edwards was bar-to-bar at each and every turn - Biaggi snatching the group lead into the sweeping turn 6 on lap 3, but a slight mistake on the exit saw him mugged by both his rivals on the uphill charge to the corkscrew, with Gibernau then appearing from nowhere to demote Max a further position before he reached the first apex of the spectacular downhill turn.
Of that group, it was new third placed man Edwards who soon proved to have the most pace, the Texan pulling quickly clear as he attempted to reign in the top two, starting with team-mate Rossi, already some two-seconds ahead. The #5 trimmed it to 1.5secs over the following laps, but then the top three seemed to hit their limits - neither able to close or drop the other.
At that stage the race looked like it could go to any of the trio, but at around one third distance Hayden broke the deadlock as he increased his lead up to 2.8secs. But Nicky wasn't the only American digging deep, with Edwards matching the race leader to close onto Rossi's rear wheel - the Italian, for the first time in a long time, looking like the weak link in the three-rider chain.
But with times so close, Edwards was in danger of becoming trapped behind the #46 - or so many thought. However, The Tornado had other ideas and would pull the kind of pass only a Laguna veteran could deliver, by neatly diving up the inside of Rossi on the entrance to the corkscrew.
Free from his team-mate, Edwards would start to slowly but surely chip away at Hayden's lead - charging to within 1.8secs of the RCV rider by lap 19. However, the effort had taken its toll on the #5's tyres and, despite his efforts to stand the yellow M1 up as soon as possible out of turns, he began to gradually lose ground to Nicky.
That marked the end of Hayden's opposition and only a mistake could deprive the former AMA Superbike champion of a maiden victory, but the #69 was simply faultless right to the flag.
Meanwhile, the closing stages saw Rossi mount a late attack on his team-mate, and the world champion would start the last lap within striking distance of the former World Superbike champion as he sought to split the US one-two.
However, it was a tough task to expect even the Italian legend to find a way past Laguna expert Edwards and, with no obvious gap available, Rossi was left to cross the line 0.4secs behind the American - and extend his title lead to 79-points. Nevertheless, the US GP marked the first time this season that Rossi has been beaten by his team-mate.