Homozygous familial hypercholesterolemia (FH) is a genetic disorder featuring a functional defect in cellular LDL receptors, marked elevation in circulating LDL concentrations, and premature atherosclerosis. The potential atherogenic role of apo B-containing lipoproteins other than LDL in this disease is indeterminate. We describe the quantitative and qualitative characteristics of Lp(a) as a function of apo(a) phenotype in a group of eight, unrelated homozygous FH patients. Plasma Lp(a) levels were significantly elevated (2.5-fold; mean 50 +/- 32 mg/dl) as compared to those in healthy subjects. The S2 isoform of apo(a) occurred most frequently (6 of eight patients); the rare B isoform presented in three patients. Plasma Lp(a) levels in homozygous FH did not correspond to those predicted by apo(a) phenotype. Analyses of the density distribution of Lp(a) and of Lp(a) particle size and heterogeneity as a function of density did not reveal any anomalies characteristic of homozygous FH. However, comparison of the hydrated density of Lp(a) particles as a function of apo(a) isoform content revealed a clear influence of isoform on this parameter; thus, in a B/S2 heterozygous patient, the density distribution of Lp(a) fractions containing isoform B alone, B and S2, and S2 alone, demonstrated that the apparent molecular weight of apo(a) plays a determining role in controlling the hydrated density and size of the resulting Lp(a) particle. Indeed, patients expressing the high molecular weight, S2 isoform uniformly displayed a dense form of Lp(a) (hydrated density approximately 1.055 g/ml). In subjects presenting two apo(a) isoforms, each isoform resided on distinct lipoprotein particles; in such cases, the plasma levels of the denser isoform predominated, suggesting differences in rates of formation, or rates of tissular catabolism, or in the plasma stability of the particles, or a combination of these mechanisms. Considered together, our data may be interpreted to suggest that the elevated circulating levels of Lp(a) in homozygous FH patients may reflect either an increased biosynthesis, or diminished catabolism via the cellular LDL receptor pathway, or a combination of both.