In this report the authors compare the cord blood lipoproteins of a newborn boy homozygote who has low density lipoprotein (LDL) receptor-defective familial hypercholesterolemia (FH) with the lipoproteins from cord blood of normal newborns. Plasma LDL-cholesterol and apoprotein (Apo)B were 612 and 233 mg/dl (vs. 31 ± 16 and 24 ± 12 mg/dl, respectively, for normals, n = 21). DDL-cholesterol/ApoB ratio was 2.6 vs. 1.4 ± 0.5. Levels of ApoA-I, ApoA-II, and HDL-cholesterol were similar to normal cord plasma. Thus, the lipoprotein abnormality is apparent at birth and is definitely present in LDL. Abnormalities in other lipoprotein, lipid, and in plasma apoprotein levels were not detected. On zonal ultracentrifugation, FH LDL was comprised of two populations [LDL(a) and LDL(b)], both faster floating than normal cord LDL [LDL(c)]. This difference was due to the larger diameters of the particles on electron microscopy [LDL(a) = 276Å ± 32 and LDL(b) = 260Å ± 38 vs. LDL(c) = 237Å ± 26, n = 200 each, mean ± 1 SD), and their higher contents of lipids relative to protein (86 and 82% vs. 74%, LDL(a), LDL(b), and LDL(c), respectively). More than 94% of the protein in both the FH and the normal preparations consisted of ApoB. FH LDL were more effective than control LDL in competing with 125I-LDL (adult) for limiting amounts of anti-LDL antibodies in radioimmunoassay. FH LDL also competed more effectively for binding to LDL receptors on cultured fibroblasts at 4°C, and FH LDL also delivered more cholesterol into the cells. Cells grown in lipoprotein-deficient serum contained 44 ± 2 μg cholesterol/mg cell protein, incubation of cells for 18 hr at 37°C in 5 μg/ml FH LDL (protein) or in normal LDL raised cellular cholesterol levels to 75 ± 2 and 60 ± 2 μg/mg, respectively. LDL isolated from the FH patient's plasma at 6 months of age and from his brother's plasma (a 5-yr-old boy FH homozygote) were similar to LDL isolated from normolipemic subjects in flotation properties, chemical composition, and immunochemical and cell reactivity. The fact that differences between normal cord LDL and FH cord LDL were present at birth, but that the differences between control and FH LDL were no longer present postnatally suggests that the altered immunologic and cell interactive properties of FH cord LDL were probably related to its unusually high contents of core lipids.