Mechanisms of chemoresistance in renal cell carcinoma include P-glycoprotein, overexpression of multidrug resistance-1 (mdr1) gene, and unstable chromosomal aberrations. In vitro exposure of resistant tumor cells to low dose hydroxyurea causes loss of chromosomal aberrations, decrease in the mdr1 gene copies, and increased sensitivity to vinblastine. Patients received continuous hydroxyurea 500 mg every Monday, Wednesday and Friday. Vinblastine 5 mg/m2 was given intravenously on days 1 and 8 every 21 days. Seventeen patients with a median age of 63 (range 40-80) received a median of 3 courses of vinblastine (range 1-14). Toxicities included: > or = grade 3 non-hematologic toxicity (1) and febrile neutropenia (2). No treatment related mortality occurred. Three patients (17.6%) had partial responses. The median survival was 38.0 weeks (95% CI = 26.9-49.1 weeks). The addition of hydroxyurea given at the dose of 500 mg orally three times weekly had no major impact on the expected antitumor effect of vinblastine.