The purpose of this study was to examine the effects of diets containing different unsaturated fatty acids (FAs) on DU145 human prostate cancer cell growth in nude mice. In Experiment 1, groups of 25 mice were fed 23% (wt/wt) fat diets containing 18% corn oil (CO)-5% linseed oil (18:2n-6 FA-rich), 18% linseed oil (LO)-5% CO (18:3n-3 FA-rich), or 18% menhaden oil (MO)-5% CO (20:5 and 22:6n-3 FA-rich), and seven days later they were injected subcutaneously with 1 x 10(6) DU145 cells. The diets were continued for six weeks. The growth rates and final weights of tumors from the 18% CO-5% LO and 18% LO-5% CO mice were similar; there was a 30% reduction in tumor growth in the 18% MO-5% CO group (p < 0.001). The tumor phospholipid FA patterns suggested that the inhibitory effect of the high-MO diet was due, at least in part, to a reduction of arachidonic acid available for prostaglandin biosynthesis. In Experiment 2, groups of 25 mice were injected with 5 x 10(5) or 1 x 10(6) DU145 cells directly into the prostate gland and fed a high-fat linoleic acid (n-6 FA)-rich or a low-fat diet for 10 weeks. At necropsy, macroscopic cancers and microscopic intraprostatic tumors were evaluated. When the initial tumor load was 1 x 10(6) cells, all but 7 of the 50 mice had developed large macroscopic tumors; the mean tumor weight in the high-fat group was twice that in the low-fat group (p = 0.047). A stimulatory effect of dietary n-6 FA on DU145 prostate cancer cell growth may require a critical initial tumor cell mass.