Male C57BL/6 mice [wild type (WT), COX‐1 null, or COX‐2 null, from Dr. R. Langenbach, n=15/group] were fed a modified AIN−93 diet containing 10% Western fat blend and either 10% olive oil (Western‐type, WD) or 10% fish oil (FO) (n=5/diet) ad libitum for 11 weeks. Colonic mucosa was stained for Ki67 marker of cellular proliferation. The epithelial proliferative zone (as fraction of crypt height) was significantly lower in COX‐1 null (0.53 ± 0.06) vs. COX‐2 null (0.67 ± 0.04) and WT (0.68 ± 0.03) mice fed WD. Similar trends were observed for Ki67‐labeling index (LI) between groups. These data suggest that the influence of fatty acids on epithelial proliferation in normal colonic mucosa is modulated by COX‐1, which is constitutively expressed. The effect of COX‐2 knockout was likely not significant due to low expression in normal mucosa. FO‐fed mice had slightly decreased proliferation that was not affected by COX status. This could be due to distinct metabolic products from n‐3 FAs in FO vs. n‐6 FAs present in the WD. Preliminary analysis of eicosanoids in the colonic mucosa indicated that COX‐1 null mice had greatly decreased PGE2 levels while levels in COX‐2 null mice were similar to that of control mice. Although FO decreased PGE2, COX‐1 knock‐out had a much stronger effect. These data have implication for prevention targets in normal mucosa. Supported by the Michigan Institute for Clinical & Health Research and NIH grant GM 48864.