This study aims to investigate the apoptotic and anti-angiogenic effect of Zoledronic acid on hormone-refractory prostate cancer cell lines. XTT cell proliferation assay used to assess cytotoxicity. Caspase 3/7 activity and DNA fragmentation were measured to verify apoptosis. Angiogenic cytokine profiles investigated using the human angiogenesis antibody array I. Administration of Zoledronic acid on PC-3 and DU-145 prostate cancer cell lines resulted in increased cytotoxicity and apoptosis with a time- and dose-related manner. Also, the administration of Zoledronic acid significantly reduced several angiogenic cytokine productions in PC-3 and DU-145 cell lines. Zoledronic acid successfully induced apoptosis and reduced various angiogenic cytokine production in hormone-refractory prostate cancer cell lines. Novel treatment protocols may be developed in the future with chemotherapeutic combinations for the treatment of prostate cancer.