We compared three different chemotherapy regimens containing epirubicin in hormonerefractory prostate cancer (HRPC) patients. Sixty-nine patients with HRPC were randomized into three groups. The first group (22 patients) received 30 mg/m2/week i.v. epirubicin for 8 weeks. The second group (24 patients) received 30 mg/m2/week i.v. epirubicin for 8 weeks followed by monthly maintenance therapy for 4–6 months. The third group (23 patients) received oral estramustine phosphate (EMP) at a dose of 840 mg/day together with weekly and monthly maintenance epirubicin. The response rates, mean survival times, and toxicity were determined. Within the first 3 months, pain and performance scores were improved by at least one degree in all the groups. One patient in group two and three patients in group three had complete response. Partial response rates were 23% in group 1, 25% in group 2, and 17% in group 3. Stable disease rates were 41% in group 1, 33% in group 2, and 26% in group 3. The progression rates within the first 3 months were 36% in group 1, 38% in group 2, and 44% in group 3. None of the patients developed complications that were significant enough to terminate the treatment. Two patients in group 3 died of cardiotoxicity. The mean survival times were 10.1, 15.8, and 16.1 months in groups 1, 2, and 3, respectively. It was determined that weekly and maintenance epirubicin treatment protocol, and estramustine treatment protocol in addition to this treatment, was only meaningfully more effective against weekly epirubicin treatment in the statistical sense (0.01 < p < 0.05). However, due to the complications of EMP, which influence the quality of life, we believe that this was usable only when measures were adopted against these effects