The combination of estramustine phosphate and vinblastine sulfate, 2 agents with separate and unique antimicrotubular effects, has demonstrated additive cytotoxicity against the DU145 human prostate derived cell line in vitro. We evaluated this combination in 25 patients with progressive hormone refractory prostate cancer. Of 24 patients with an elevated prostate specific antigen (PSA) level at the start of treatment 13 (54%, 95% confidence limits 34 to 74%) had a greater than 50% decrease in PSA levels on at least 3 consecutive biweekly determinations. The median decrease in PSA in responding patients was 64% (mean 71.7%) and the median duration of response was 7 months. In 5 patients with bidimensionally measurable disease 2 partial responses were observed. Treatment was well tolerated, with mild and manageable toxicity. This is a well tolerated outpatient treatment regimen for patients with hormone-refractory prostatic cancer which deserves further investigation.