PEDF is a secreted glycoprotein previously shown to act as an endogenous inhibitor of angiogenesis in the eye. Studies demonstrate that PEDF is also a potent angiogenic inhibitor in the prostate, expressed by both epithelial and stromal compartments and regulated by hypoxia and androgens in vitro. Interestingly, PEDF protein expression increased in vivo following castration of normal rats and in postandrogen ablation therapy in human prostate cancer tissue. Loss of inhibitory PEDF contributed to high angiogenic activity in media conditioned by prostate cancer cells, whereas treatment with PEDF limited the growth of xenograft tumors. The importance of PEDF in the prostate was underscored when prostatic hyperplasia was evident in PEDF null mice. As an androgen- and hypoxia-sensitive factor, PEDF may participate in paracrine and autocrine pathways that curtail prostate growth.