A role of adiponectin in tumorigenesis has recently been appreciated. Although plasma adiponectin levels in subjects with prostate cancer have been found to be significantly lower than in subjects with benign prostatic hyperplasia or in normal healthy controls, the underlying molecular mechanisms remain unknown. Here, we not only detected significant decreases in plasma adiponectin levels in prostate cancer patients, but also showed significant decreases in adiponectin receptor I (AdipoR1) levels in the resected prostate cancer specimen. Prostate cancer cell lines examined in the current study had all lower levels of adiponectin and AdipoR1, compared to normal healthy prostate tissue. Moreover, overexpression of adiponectin in prostate cancer cells decreased production of vascular endothelial growth factor A (VEGF-A), while adiponectin depletion increased VEGF-A. Furthermore, adiponectin seemed to activate AMPK/TSC2 to inhibit mTor-mediated activation of VEGF-A. Taken together, our data suggest that adiponectin may play an essential role in suppressing growth of prostate cancer cells through inhibition of VEGF-A-mediated cancer neovascularization.