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Preclinical studies suggest lowering dietary fat and decreasing the ratio of omega-6 to omega-3 polyunsaturated fatty acids decreases the risk of prostate cancer development and progression. We conducted a phase II randomized trial to test the effect of decreasing dietary fat combined with decreasing the dietary omega-6:omega-3 ratio on biomarkers related to prostate cancer development and progression. Patients undergoing radical prostatectomy were randomly assigned to receive a low-fat diet with 5 grams of fish oil daily (dietary omega-6:omega-3 ratio of 2:1) or a control western diet (omega-6:omega-3 ratio of 15:1) for 4–6 weeks prior to surgery. The primary endpoint was change in serum IGF-1 between arms. Secondary endpoints were serum IGFBP-1, prostate prostaglandin E-2 levels, omega-6:omega-3 fatty acid ratios, COX-2 and markers of proliferation and apoptosis. Fifty-five patients were randomized and 48 completed the trial. There was no treatment difference in the primary outcome. Positive secondary outcomes in the low-fat fish oil vs. western group were reduced benign and malignant prostate tissue omega-6:omega-3 ratios, reduced proliferation (Ki67 index), and reduced proliferation in an ex-vivo bioassay when patient sera was applied to prostate cancer cells in vitro. In summary, 4–6 weeks of a low-fat diet and fish oil capsules to achieve an omega-6:omega-3 fatty acid ratio of 2:1 had no effect on serum IGF-1 levels, though in secondary analyses the intervention resulted in decreased prostate cancer proliferation and decreased prostate tissue omega-6:omega-3 ratios. These results support further studies evaluating reduction of dietary fat with fish oil supplementation on modulating prostate cancer biology.