Androgen-independent, castration-resistant prostate cancer (CRPC) invariably occurs and the outcome is poor. The specific effect and mechanism of abiraterone on the cell proliferation of androgen-independent prostate cancer remains elusive. A number of studies have already reported glycolysis driving prostate tumorigenesis. To address the specific role of abiraterone on glycolysis in androgen-independent prostate cancer, metabolic studies combined with gene expression analysis were performed in vitro. We demonstrated abiraterone increases cell proliferation via promoting glycolysis (the Warburg effect) in PC-3 and PC-3M 1E8 of androgen-independent prostate cancer cell. Abiraterone-induced cell proliferation and glycolysis in Smad3-dependent. We also found that abiraterone can enhance the interaction between Smad3 and HIF-1α, activate Smad3, and induce the expression of HIF-1α. This study indicated that abiraterone may promote positive feedback loop of Smad3/HIF-1α transcriptional complex \p-Smad3\HIF-1α, which implies the contribution of tumor glycolysis and proliferation, which may lead to a breakthrough in the treatment of prostate cancer (Figure A).