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T he d < 1.006 lipoproteins of patients in a kindred with atypical dysbetalipoproteinemia induced marked cholesteryl ester accumulation in mouse peritoneal macrophages. The affected family members had severe hypercholesterolemia and hypertriglyceridemia, xanthomatosis, premature vascular disease, the apo-E3/3 phenotype, and a predominance of cholesterol-rich β-very low density lipoproteins (β-VLDL) in the d < 1.006 fraction. When incubated with mouse peritoneal macrophages, the d < 1.006 lipoproteins or β-VLDL from the affected family members stimulated cholesteryl [¹⁴C]oleate synthesis 15- to 30-fold above that caused by normal, control d < 1.006 lipoproteins (VLDL). The ability of the β-VLDL to stimulate macrophage cholesteryl ester accumulation was greatly reduced as a consequence of treatment with hypolipidemic agents, which specifically reduced the concentration of β-VLDL. Two important differences were noted in a comparison of the β-VLDL from these atypical dysbetalipoproteinemic subjects with that of classic E2/2 dysbetalipoproteinemics: (a) the β-VLDL from the atypical subjects were severalfold more active in stimulating cholesteryl ester accumulation in macrophages, and (b) both the intestinal and hepatic β-VLDL from the atypical subjects were active. The triglyceriderich, α₂-migrating VLDL from the affected family members constituted <10% of the d < 1.006 fraction and were similar to normal VLDL in that they did not stimulate cholesteryl ester synthesis in the macrophages.Several lines of evidence indicate that the macrophage accumulation of cholesteryl esters was induced by a receptor-mediated uptake process and that the β-VLDL were bound by a specific β-VLDL receptor. First, the uptake and degradation of the lipoproteins and the induction of cholesteryl ester formation displayed qualities of high affinity, saturable kinetics. Second, the uptake and degradation process was inhibited when the lysyl residues of the β-VLDL apoproteins were modified by reductive methylation. Third, the β-VLDL from the affected subjects competed with diet-induced canine ¹²⁵I-β-VLDL for the same cell surface receptors, but did not compete with chemically modified low density lipoproteins. Finally, the receptor-mediated uptake of these β-VLDL resulted in lysosomal degradation of the lipoproteins, which could be prevented by incubating the cells with chloroquine. Normal, triglyceride-rich VLDL were also degraded when incubated with the macrophages, but they were not degraded by the same receptor-mediated process responsible for the degradation of the β-VLDL of the patients. The degradation of the VLDL was not abolished by reductive methylation of the lipoproteins or by treatment of the cells with choloroquine. These studies demonstrate that the β-VLDL from subjects with atypical dysbetalipoproteinemia are taken up by macrophages via the same receptor-mediated process responsible for the uptake of diet induced β-VLDL. The accelerated vascular disease seen in these patients may be the result of high concentrations of β-VLDL capable of binding to and delivering large quantities of cholesterol to macrophages and converting them into cells resembling the foam cells of atherosclerotic lesions.