Zinc finger protein X-linked (ZFX) is a highly conservative mammalian gene with related functions in cell survival and proliferation. However, there are limited reports on regulation of ZFX as a therapeutic target in cancer treatment. In this study, the expression of ZFX in prostate cancer with matched normal adjacent tissues (n=45) and benign prostatic hyperplasia (BPH) tissues (n=16) were observed by immunohistochemical analysis. The effect of lentiviral siRNA (small interference RNA)-mediated dysfunction of ZFX on the proliferation of prostate cancer cells was studied. ZFX mRNA and protein expression levels in prostate cancer cells (PC-3 and DU145) were analyzed by western blotting and real-time polymerase chain reaction (RT-PCR). The effects of siRNA targeting ZFX on growth, cell cycle and apoptosis of PC-3 cells were evaluated by MTT assay and flow cytometry. We also investigated the effect of ZFX deletion on the activation of caspase-1, -3 and -9 by western blotting and colorimetric assay. Prostate cancer specimens appeared significantly higher (42.2% of cases being positive) than that observed in normal adjacent tissues (11.8% of cases being positive) and BPH tissues (12.5% of cases being positive). Repression of ZFX in the prostate cancer cells effectively suppressed the cellular proliferation and colony-formation ability, and led to G1 phase cell cycle arrest. Moreover, inhibition of ZFX-induced cell apoptosis by activating caspase-1, -3 and -9. In conclusion, ZFX represents the prominent role in the progression of prostate cancer and may be a promising therapy target for prostate cancer.