Roddick, who won the tournament three years ago, scored a 7-6 (7-5), 7-6 (7-3) victory to set up a quarterfinal meeting with Robin Soderling.
Soderling was a 6-1, 6-2 winner over qualifier Christophe Rochus.
Second-seeded Richard Gasquet was ousted from the event by Steve Darcis 6-4, 3-6, 7-6 (7-5). No 3 seed Jo-Wilfried Tsonga advanced by defeating Fabrice Santoro 6-2, 5-7, 6-3.
Tsonga will have a quarterfinal meeting with former world No. 1 Juan Carlos Ferrero, a 6-4, 6-1 winner over Paul-Henri Mathieu.
Ferrero captured the Lyon event 11 years ago.