A diet containing 20% by weight of fat rich in unsaturated fatty acids reduced the ability of guinea pigs to form antibody and the delayed hypersensitivity response in vivo against a single antigen. Reduced responses in vivo are manifested on first challenge only, subsequent antigenic challenges showed responses similar to those of animals fed a normal diet. However, cells from animals fed large amounts of unsaturated fats when cultured in vitro with antigen and sera of normal animals fed a low-fat diet did not show reduced delayed hypersensitivity (macrophage migration inhibition and lymphocyte transformation). The serum of animals fed high-fat diets greatly inhibited the response to mitogens and to antigen in vitro of lymphocytes from tuberculin-sensitized animals fed either low or high-fat diet. As serum from animals fed low-fat diets did not have this effect, it is postulated that the inhibitory activity is due to a lipid or lipoprotein derivative of unsaturated fatty acids. Animals fed high-fat diets remained healthy, and showed no disorder related to the fat and no susceptibility to infection.