Cancer and Leukemia Group B 19808 (CALGB 19808) is the only randomized trial of a second-generation P-glycoprotein (Pgp) modulator in untreated patients with acute myeloid leukemia (AML) younger than age 60 years. We randomly assigned 302 patients to receive induction chemotherapy regimens consisting of cytosine arabinoside (Ara-C; A), daunorubicin (D), and etoposide (E), without (ADE) or with (ADEP) PSC-833 (P). The incidence of complete remission was 75% with both regimens. Reversible grade 3 and 4 liver and mucosal toxicities were significantly more common with ADEP. Therapy-related mortality was 7% and did not differ by induction arm. Excess cardiotoxicity was not seen with high doses of D in ADE. The median disease-free survival was 1.34 years in the ADE arm and 1.09 years in the ADEP arm (P = .74, log-rank test); the median overall survival was 1.86 years in the ADE arm and 1.69 years in the ADEP arm (P = .82). There was no evidence of a treatment difference within any identifiable patient subgroup. Inhibition of Pgp-mediated drug efflux by PSC-833 did not improve clinical outcomes in younger patients with untreated AML. This trial was registered at www.clinicaltrials.gov as #NCT00006363.