The acute phase reactant serum amyloid A protein (SAA) circulates in plasma as a constituent of high density lipoproteins (HDL). Advantage has been taken of the induction of SAA in human subjects with myocardial infarction to study the effect of SAA on the physical and chemical properties of HDL. HDL were isolated by sequential ultracentrifugation and assayed for chemical composition. Apolipoprotein composition was assessed by SDS polyacrylamide gel electrophoresis. Size distribution of HDL was determined by gradient gel electrophoresis and density distribution by density gradient ultracentrifugation. In studies of 18 subjects with myocardial infarction, SAA accounted for 8-87% (median 52%) of the HDL apolipoprotein. These SAA-enriched HDL had a density comparable to that of normal HDL subfraction-3 (HDL3). Their chemical composition differed from normal HDL3, however, with a reduced phospholipid (17% vs 24%) and an increased triglyceride (7.7% vs 1.6%) value. When separated by gradient gel electrophoresis, the SAA-enriched HDL were much larger than normal HDL3, having a radius of 4.5-5.3 nm that extended well into the size range of HDL2; particle size correlated with SAA content. This disassociation between particle density and particle size was also observed with the SAA-enriched HDL isolated from a subject with secondary amyloidosis and also with normal HDL that had been enriched with SAA during incubation in vitro. Thus, the presence of high levels of SAA has been found to be associated with phospholipid-depleted particles of a density comparable to HDL3 but a size larger than normal HDL3.