Thirty-one patients with progressive metastatic prostate cancer refractory to first- or second-line hormonal therapy were treated with a combination of daily oral estramustine phosphate (600 mg) and weekly intravenous doxorubicin (20 mg/m2). Eighteen (58%) patients demonstrated a biologic response with a 50% or more serum prostate-specific antigen decline. The median duration of biologic response was three months. Five (45%) of the 11 patients with measurable lesions achieved a partial response in liver or retroperitoneal lymph nodes. The median duration of these objective responses was four months. Of 22 patients who required analgesics at the onset of the study, six (27%) achieved a significant reduction of pain. The combination of doxorubicin and estramustine phosphate was tolerated on an outpatient schedule. The occurrence of severe toxicities required suspension of therapy in six patients. At the end of the observation time, all patients but one had died, 29 of progressive prostatic cancer and one of toxicity. The median survival time from the onset of chemotherapy was 12 months. The administration of weekly doxorubicin with phosphate estramustine appears to be a safe combination for those patients with hormone-resistant prostate cancer who require chemotherapy. The benefit of chemotherapy should be investigated using relevant quality-of-life criteria in future trials.