Del Potro lost his serve twice in the first set of a 1-6, 6-3, 6-4 decision over Nicolas Mahut. He had 14 of his 15 aces and won nearly two-thirds of the points on serve the rest of the way.
No. 4-seeded Dmitry Tursunov also needed three sets to get by Lukas Rosol 3-6, 6-3, 6-3 as seeded players went 2-4 Wednesday in the second round in Sydney.
Alexandr Dolgopolov roared past second-seeded Jerzy Janowicz 6-2, 6-2 in 56 minutes. Dolgopolov lost only seven points in eight games serving and broke Janowicz's serve four times.
Marinko Matosevic also didn't drop serve in a 6-3, 6-4 upset of third-seeded Andreas Seppi while Sergiy Stakhovsky took out No. 6-seeded Julien Benneteau 6-3, 6-2 and Denis Istomin was a 6-3, 6-4 winner over Marin Cilic, the No. 7 seed.
Radek Stepanek grabbed a quarterfinal spot opposite del Potro with a 6-2, 7-6 (7-5) decision over Albert Ramos and defending champion Bernard Tomic edged by Blaz Kavcic 6-3, 4-6, 6-4 in Wednesday's other matches.