Objective: Docetaxel has become the standard of care for hormone-refractory prostate cancer (HRPC), however drug resistance and toxicity are still challenging in daily cancer practice. The anti-apoptotic pathway centered around the Bcl-2 protein might be one of the responsible pathways. Adding a second drug to docetaxel treatment is one of the most common approaches to solve this problem. Gossypol was reported to have potent anticancer activities in prostate cancer. In this study, we searched for the possible synergistic cytotoxic/apoptotic effects of this combination treatment in hormone- and drug resistant prostate cancer cell line, DU-145 via inhibition of Bcl-2 protein. Material and Methods: XTT cell viability assay was used to assess cytotoxicity of the drugs alone and in combination. For verifying apoptosis, Cell Death Detection Elisa Plus Kit and Caspase-Glo 3/7 assay were used. Western Blot analysis for Bcl-2 protein was carried out. Results: A novel drug combination of docetaxel and gossypol resulted in a significant synergistic cytotoxic activity and apoptosis as compared to any single agent alone, in a dose- and time dependent manner, and also significantly reduced Bcl-2 protein levels in DU-145, in doses that can be used clinically. Condusion: Adding gossypol to docetaxel as a combination treatment in HRPC patients might be a solution for taxane resistant patients. Inhibition of Bcl-2 might be one of the underlying routes of activity for this combination.