Omega-3 fatty acids, abundant in fish oil, are reported to alter membrane properties when incorporated into membrane phospholipids. We report that dietary omega-3 fatty acids, incorporated into tumor cell membranes, alter tumor recognition and cytolysis by the immune system. Mice were fed diets rich in corn oil, hydrogenated coconut oil, or menhaden (fish) oil. T27A leukemia cells were grown as an ascites tumor in these mice and harvested for biochemical and immunologic assays. The incorporation of the long-chain omega-3 fatty acid docosahexaenoic acid (22:6) into tumor plasma membranes correlated with an increased susceptibility to tumor cytolysis by alloreactive cytotoxic T lymphocytes and decreased expression of a class I major histocompatibility complex epitope, monitored by complement-mediated lysis and radioimmunoassay. Thus the immunologic phenotype of this ascites tumor reflected the source of oil present in the diet during tumor growth.