Antibodies to malondialdehyde (MDA)-modified low-density lipoprotein (LDL) are transiently reduced during the postprandial period in patients with atherosclerotic heart disease. Previous experiments using mixed meals high in fat have found reductions of approximately 20% within 2 hours. This study was designed to reveal if this phenomenon was due uniquely to saturated fats. Using a standardized immunoassay for the detection of circulating levels of autoantibodies (AAbs) against MDA-modified LDL, we examined the acute changes in AAb levels during 6 hours of postprandial lipemia in 10 men with known atherosclerotic heart disease. Each subject was given 4 meals 1 week apart. Three of the meals differed in content of saturated fat, monounsaturated fat, and polyunsaturated fat. A fat-free meal with equivalent carbohydrate and equivalent protein was also administered. The study was double blinded and the meals were administered in random order. Only the meal enriched with polyunsaturated fatty acids caused the reduction in antibodies to MDA-LDL. This decrease was statistically significant from baseline at 1 hour (p <0.05), 2 hours (p <0.004), and 3 hours (p <0.02), with the nadir occurring at 2 hours. Polyunsaturated fatty acids are the major stimulus for causing a reduction in the AAbs to MDA-LDL during postprandial lipemia. These results strongly suggest that fat in chylomicrons may be a major source of oxidized lipids in the blood of patients with arteriosclerosis.