The Lp(a) lipoprotein represents a quantitative genetic trait. It contains two different polypeptide chains, the Lp(a) glycoprotein and apo B-100. We have demonstrated the Lp(a) glycoprotein directly in human sera by sodium dodecyl sulfate-gel electrophoresis under reducing conditions after immunoblotting using anti-Lp(a) serum and have observed inter- and intraindividual size heterogeneity of the glycoprotein with apparent molecular weights ranging from approximately 400,000-700,000 D. According to their relative mobilities compared with apo B-100 Lp(a) patterns were categorized into phenotypes F (faster than apo B-100), B (similar to apo B-100), S1, S2, S3, and S4 (all slower than apo B-100), and into the respective double-band phenotypes. Results from neuraminidase treatment of isolated Lp(a) glycoprotein indicate that the phenotypic differences do not reside in the sialic acid moiety of the glycoprotein. Family studies are compatible with the concept that Lp(a) glycoprotein phenotypes are controlled by a series of autosomal alleles (Lp[a]F, Lp[a]B, Lp[a]S1, Lp[a]S2, Lp[a]S3, Lp[a]S4, and Lp[a]0) at a single locus. Comparison of Lp(a) plasma concentrations in different phenotypes revealed a highly significant association of phenotype with concentration. Phenotypes B, S1, and S2 are associated with high and phenotypes S3 and S4 with low Lp(a) concentrations. This suggests that the same gene locus is involved in determining Lp(a) glycoprotein phenotypes and Lp(a) lipoprotein concentrations in plasma and is the first indication for structural differences underlying the quantitative genetic Lp(a)-trait.