The n-6 and n-3 families of fatty acids serve as precursors in the formation of mediators observed in inflammation. Eicosanoids from the cyclooxygenase and lipoxygenase pathways have been shown to influence natural killer (NK) cell activity. In this study, rats were fed diets either deficient in essential fatty acids (EFAD), or diets that contained marine oil (15% menhaden, MEN) or safflower oil (15% safflower, SAF). Rats were then subjected to either in vivolipopolysaccaride (LPS) or a sham procedure. LPS treated animals had higher (p < 0.05) NK activity than those of the sham group. EFAD-fed animals had higher (p < 0.05) NK activity than animals fed diets containing lipids. Dietary treatment and LPS interactions were not significant, indicating that major shifts in cell lipid concentrations did not alter endotoxin-induced enhancement of NK activity. Rats fed EFAD diets had enhanced NK activity in both sham and LPS-treated animals.