We earlier provided evidence that oral consumption of pomegranate fruit extract (PFE) inhibits prostate cancer (PCa) cell growth in nude mice. To ascertain convincing evidence of chemopreventive effects of PFE against PCa, its efficacy requires to be evaluated in animal models that closely emulate human disease. Here, we provide evidence of remarkable tumor growth inhibitory effects of PFE using the TRAMP model. Mice received 0.1 and 0.2% PFE, equivalent to 250 and 500 ml of pomegranate juice, in drinking water, starting at 6 weeks and examined at 12, 20 and 34 weeks of age. In water-fed group, 100% mice developed palpable tumors by 20 weeks compared with only 30 and 20% in the 0.1 and 0.2% PFE-supplemented groups, respectively. At 34 weeks, palpable tumors were observed in 70 of 0.1% and only 50 of 0.2% PFE-supplemented mice. Compared with median survival of 43 weeks in water-fed mice, 0.1 and 0.2% PFE-supplemented mice exhibited median life expectancy of 73 and 92 weeks, respectively. Compared with respective water-fed groups, none of the mice in PFE-supplemented groups exhibited metastases to any of the distant organs at 20 weeks and only 20% mice exhibited metastasis at 34 weeks of age. Many of the PFE-supplemented animals had multiple foci of well-differentiated carcinoma but no evidence of poorly differentiated carcinoma. PFE supplementation resulted in simultaneous and significant inhibition of IGF-I/Akt/mTOR pathways in the prostate tissues and tumors. We suggest that pomegranate juice be evaluated in clinical trials in patients at high risk for developing PCa.