BACKGROUND The tumor suppressor gene p53 is implicated in cell cycle control and apoptosis. Antagonists of growth hormone‐releasing hormone (GHRH) have been shown to inhibit human experimental prostate cancers. METHODS We investigated the involvement of p53 apoptotic pathways in this effect. Nude mice bearing xenografted PC‐3, DU‐145, and MDA‐PCa‐2b human prostate cancer lines were treated with a new potent GHRH antagonist MZ‐J‐7‐138. To determine whether tumor inhibition by MZ‐J‐7‐138 involves apoptotic mechanisms such as p53 and p21, we evaluated by Western Blot the expression of mutant mt‐p53 in PC‐3 and DU‐145 and of wild type (wt‐p53) in MDA‐PCa‐2b prostate cancers as well as p21. RESULTS MZ‐J‐7‐138 significantly inhibited the growth of PC‐3, DU‐145, and MDA‐PCa‐2b xenografts in nude mice. Androgen deprivation with the LHRH antagonist Cetrorelix enhanced the anti‐proliferative effect of GHRH antagonist MZ‐J‐7‐138 on MDA‐PCa‐2b tumors. The expression of mutant (mt‐p53) and p21 protein in PC‐3 and DU‐145 tumors was significantly decreased by treatment with MZ‐J‐7‐138, whereas wild type wt‐p53 expression in MDA‐PCA‐2b tumors was up regulated by treatment with Cetrorelix. All three models investigated expressed specific, high affinity GHRH receptors. CONCLUSIONS Our findings indicate that the anti‐proliferative effects of GHRH antagonist MZ‐J‐7‐138 and LHRH antagonist Cetrorelix on prostate cancers involve p53 and p21 signaling. Prostate 72:555–565, 2012. © 2011 Wiley Periodicals, Inc.