Armstrong finished the 9.6-mile climb through 21 hairpin turns to the L'Alpe d'Huez ski station in 39 minutes, 42 seconds — the only rider under 40 minutes.
"I wanted it bad because of the history around this mountain and the importance to the race," Armstrong said. "All in all, it was a very important day."
He was 61 seconds faster than second-place Jan Ullrich and actually passed his closest challenger, Ivan Basso, even though the Italian started two minutes ahead of the Texan.
"Lance is strong in the mountains," acknowledged Basso, who was eighth Wednesday, 2:23 behind, and now trails by 3:48 in the overall standings.
It was Armstrong's second consecutive stage victory and third during the Tour, and at this point, only a disaster would appear to stand in the way of his record sixth straight title when the cycling marathon ends in Paris on Sunday.
Behind Basso, Andreas Kloden is third overall, 5:03 back, with Ullrich — the 1997 champion and five-time runner-up — fourth, 7:55 off Armstrong's pace. Last year, Armstrong finished just 1:01 ahead of Ullrich.
But no one came close to Armstrong's performance Wednesday. Wearing black shoes, black socks and his coveted yellow jersey, which he reclaimed by winning Tuesday's 15th stage in the mountains, Armstrong was relentless.
As the overall leader, he had the advantage of being the last cyclist to start the individual race against the clock, so he had a chance to measure himself against his opponents. In particular, of course, his eyes were on second-place Basso, who set out on the ascent two minutes ahead of Armstrong.
Mouth open, silver chain dangling out of his unzipped jersey, Armstrong caught up to Basso and passed him just after riding over a red-white-and-blue Texas state flag drawn on the black pavement. Basso glanced to left at Armstrong, who just looked straight ahead.
At the bottom of the climb, crowds completely covered the road, parting only at the very last second as riders hurtled toward them. Some fans ran alongside the bicycles, waving flags that came close to catching handlebars or wheels. Others were slow to move aside, forcing riders to swerve.
Police motorcyclists rode in front of the racers, sirens blaring, parting the crowds somewhat. But every moment still seemed to be an accident waiting to happen.
"The crowds were animated, I should say," Armstrong said. "Although I enjoyed my day, I still think it's a bad idea to have a time trial on this mountain."