Hewitt, playing in this tournament for the first time, was beaten by Pablo Andujar of Spain 6-3, 4-6, 6-3. Seppi fell to Yen-Hsun Lu of Taiwan 7-5, 1-6, 6-4. Lu will next play Andujar, a semifinalist at this month's Madrid Open.
Carlos Berlocq of Argentina and Robin Haase of the Netherlands also advanced. Haase faces fourth-seeded John Isner of the U.S. in the next round.
Berlocq didn't face a break point in his 6-2, 6-1 victory over Leonardo Mayer. Haase beat Marinko Matosevic of Australia 6-1, 6-4.
Victor Hanescu of Romania outlasted Albert Ramos of Spain 6-3, 5-7, 6-4. The 2011 runner-up will meet Albert Montanes of Spain.