The 30-year-old Texan completed the 7-kilometer (4.34-mile) individual time-trial in 9 minutes and 8 seconds, topping Frenchman Laurent Jalabert by nearly 2 seconds. Raimondas Rumsas of Lithuania was third, 3 seconds behind Armstrong.
Armstrong, of the U.S. Postal Service team, rode during a break in rain that had threatened to make the course slick.
``The weather was so-so ... but I saw that the sun was coming out just before I started,'' Armstrong said in a faltering French on France-2 Television shortly after the win. As reigning champion, Armstrong was the last rider to take the start.
Shortly before he rode down the starting ramp, Armstrong began his warmup with his wife, Kristin, and his three children in the practice area - the first time his family has been at his side for the Tour start.
``It's a great motivator to be in the warmup with the twins and Luke,'' he said. The Texan has twin daughters.
Asked whether he would try defending his yellow jersey in the next few stages, Armstrong said, ``I think probably not. We'll wait for the team time-trial (on Wednesday).''
Thousands of cycling fans looked on and cheered as riders raced through the streets of Luxembourg.
Prologue results, top 10:
1. Lance Armstrong (USA) US Postal 09min 08sec
2. Laurent Jalabert (Fra/CST) at 00:02.
3. Raimondas Rumsas (Lit/LAM) 00:03.
4. Santiago Botero (Col/KEL) 00:04.
5. David Millar (Gbr/COF) 00:05.
6. Laurent Brochard (Fra/DEL) 00:06.
7. Dario Frigo (Ita/TAC) 00:08.
8. Igor Gonzalez Galdeano (Spa/ONE) 00:09.
9. Joseba Beloki (Spa/ONE) 00:13.
10. Laszlo Bodrogi (Hun/MAP) 00:13.
Prologue: Post-stage commentary