Taxol is the first-line chemotherapeutic agent for patients with castration-resistant prostate cancer. However, the mechanism of the sensitivity of prostate cancer cells to Taxol treatment remains to be elucidated. In the present study, it was found that paclitaxel induced more apoptosis and maspin expression in phosphatase and tensin homolog (PTEN)-positive 22Rv1 cells than PTEN-negative LNCaP cells. Knockdown of PTEN in 22Rv1 cells resulted in increased resistance to paclitaxel and impaired the induction of maspin expression by paclitaxel. Overexpression of PTEN sensitized LNCaP cells to paclitaxel treatment and increased maspin induction by paclitaxel. Furthermore, knocking down maspin abrogated PTEN-induced paclitaxel sensitivity in LNCaP cells. PTEN/maspin signaling may be important for regulating the susceptibility to paclitaxel in prostate cancer.