Animal models suggest that n-3 fatty acids inhibit prostate cancer proliferation, whereas n-6 fatty acids promote it, but epidemiologic studies do not uniformly support these findings. Methods: A nested case-control study was conducted among 14,916 apparently healthy men who provided blood samples in 1982. Blood fatty acid levels were determined for 476 men diagnosed with prostate cancer during a 13-year follow-up and their matched controls. Conditional logistic regression was used to estimate the relative risks (RR) and 95% confidence intervals (95% CI) of total, non-aggressive (stage A/B and Gleason <7) and aggressive (stage C/D, Gleason z7, subsequent distant metastasis or death) prostate cancer associated with blood levels of specific fatty acids expressed as percentages of total fatty acids. Results: Whole blood levels of all long-chain n-3 fatty acids examined and of linoleic acid were inversely related to overall prostate cancer risk (RRQ5vs.Q1, 0.59; 95% CI, 0.38-0.93; Ptrend = 0.01 for total long-chain n-3 fatty acids and RRQ5vs.Q1, 0.62; 95% CI, 0.41-0.95; Ptrend = 0.03 for linoleic). Blood levels of ;-linolenic and dihomo-;-linolenic acids, fatty acids resulting from the metabolism of linoleic acid, were directly associated with prostate cancer (RR, 1.41; 95% CI, 0.94-2.12; Ptrend = 0.05 for ;-linolenic and RR, 1.54; 95% CI, 1.03-2.30; Ptrend = 0.02 for dihomo-;-linolenic acid). Levels of arachidonic and A-linolenic acids were unrelated to prostate cancer. Conclusions: Higher blood levels of long-chain n-3 fatty acids, mainly found in marine foods, and of linoleic acid, mainly found in non-hydrogenated vegetable oils, are associated with a reduced risk of prostate cancer. The direct associations of linoleic acid metabolites with prostate cancer risk deserve further investigation
