The 32-year-old Jamaica left-hander made 53 in just 51 balls with five sixes and three fours before he fell lbw to off-spinner Graeme Swann.
Gayle, arguably the world's best limited overs opener, had not played an international match for 15 months following a dispute with West Indies Cricket Board officials.
But having missed the 114-run defeat in the first one-dayer at Southampton with a shin injury, Gayle -- back in place of the injured Darren Bravo -- showed just what the West Indies had been missing since his last international appearance at the 2011 World Cup
However, he started cautiously, with the West Indies scoring just 14 runs in the first five overs after England captain Alastair Cook had opted to field after winning the toss.
But 48 runs came in the next six overs as Gayle cut loose.
The onslaught started when Gayle struck three fours in as many balls off fast bowler Steven Finn, a glance followed by a slice over the slips and a drive through mid-on.
He then pulled James Anderson, who had started with two maidens, for six.
First change Tim Bresnan's opening over went for 18 runs as Gayle struck three sixes, drives off successive balls over long-on and long-off followed by a huge hit onto the roof of the Bedser stand where the former West Indies captain had lofted Australia fast bowler Brett Lee during the 2009 World Twenty20.
England, who'd conceded just eight runs in the first five overs, saw 48 scored in the next six with Lendl Simmons, West Indies' other opener still in single figures when Gayle reached fifty.
But England got the wicket they so badly wanted when Gayle pushed tentatively at a Swann ball, bowled from around the wicket.
Swann let fly with a raucous and lengthy appeal and, eventually, New Zealand umpire Tony Hill raised his finger.
Gayle immediately reviewed the decision and while replays indicated an inside edge, there was no clear evidence as to whether the ball had hit the pad first.
Tracking technology indicated the ball would have hit the stumps and third umpire Kumar Dharmasena of Sri Lanka told Hill he could uphold his verdict.
A stunned Gayle lingered at the wicket for several moments before slowly trudging off, with many spectators almost as disappointed as he was his innings was over. West Indies were then 63 for one in the 15th over.
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