Hormone refractory prostate carcinoma is an incurable disease. Therapy affecting the tissue matrix at the level of the cytoskeleton has been demonstrated to inhibit prostate cancer growth. In vivo and in vitro evidence demonstrated vinblastine and tamoxifen to be agents that would interact to inhibit prostate cancer growth by microtubule inhibition. This study evaluated the effectiveness of these agents in combination in 22 patients with metastatic hormone refractory prostate cancer. Patients received tamoxifen 20 mg twice daily continuously plus vinblastine 4 mg/m2 on days 1, 8, 15, 22, 28, and 35 every 49 days. Disease response was assessed after the first two cycles of therapy. No partial or complete responses were definitively identified. Only 23% of participants received two or more full cycles of therapy. Major toxicities included grade 1-3 leukopenia (73%), grade 2-3 anemia (64%), and two participants experienced a grade 3/4 thrombocytopenia. Only two participants experienced a greater than 50% decrease in serum PSA, one of which may have been attributed to a flutamide withdrawal syndrome. We conclude that the dosage and schedule of vinblastine and tamoxifen used in this study is inactive in the treatment of metastatic hormone refractory prostate cancer.