12th-seeded Roddick fell in straight sets to Frenchman Simon in just one hour and 22 minutes and has yet to record a win on the European red clay this season after losing to qualifier Flavio Cipolla in last week's Madrid Open.
Simon won 6-3 6-3 and hit 23 winners in the match while the American managed 27 unforced errors.
Simon will now go on to face either Argentine Juan Ignacio Chela or American John Isner.
This defeat comes on a day when there are no American men or women in the top 10 in the world rankings for the first time in the 38-year history of the rankings.
Mardy Fish and Roddick are No. 11 and 12 respectively while on the women's side Serena and Venus Williams are flying the flag at No. 17 and 19.
