Patients with advanced-stage favorable-histology (FH) Wilms' tumor have a 4-year relapse-free survival rate of 70% to 90% after resection and chemotherapy of actinomycin D, vincristine, and doxorubicin. These three agents are actively pumped out of cells by P-glycoprotein (Pgp). The authors studied whether Wilms' tumor expresses Pgp and if the degree of Pgp expression correlates with treatment outcome. At the time of diagnosis, eight blinded paraffin-embedded FH and four anaplastic (ANA) Wilms' tumor sections were immunogold-labeled with a Pgp monoclonal antibody (17F9). Four of the FH-tumor patients had had relapse (FH+) according to the National Wilms' Tumor Study-3 protocol. Negative-relapse FH-tumor patients (FH-) had at least 6 years of follow-up. All 12 Wilms' tumors stained positive for Pgp. Both differentiated tubular structures and blastemal elements expressed Pgp. By the pathologist's score and the computerized cell image analysis, the degree of Pgp staining was greater at the time of diagnosis in FH+ tumors than in FH- tumors (P < .03; Mann-Whitney test). There was no statistically significant difference between ANA and FH+ or FH- tumors. These results show that both FH and ANA Wilms' tumors express Pgp, with higher levels of Pgp expression found in FH patients who had relapse. Current chemotherapeutic protocols, using Pgp-sensitive agents, may not be optimal for all FH Wilms' tumor patients.