Human group-specific component (Gc) is the plasma transport protein for vitamin D; in addition, polymorphic electrophoretic variants of Gc are found in all human populations. Because of its physiologic importance and in view of the extensive genetic variation at the Gc locus, we have determined the heritability of quantitative variation in Gc by comparing a series of monozygotic (MZ) and dizygotic (DZ) twins of known Gc genotype. The series included 31 MZ twin pairs, 13 DZ twin pairs, and 45 unrelated controls. Since Gc concentration is increased by estrogens, pregnant women and women taking oral contraceptives were excluded. We found no age-related differences in Gc concentration or differences between males and females, but the concentrations of Gc in the three electrophoretically determined genotypes were significantly different from each other. Using classical methods of heritability analysis, the overall heritability of variation in Gc concentration is approximately 70%. Heritability in males is greater than in females, probably reflecting the additional environmental effect of estrogens in women. To determine if the differences in Gc concentration between the three genotypes explain the high heritability, a new variance decomposition procedure was developed following classical methods in quantitative genetics. Application of this method suggests that 19% of the total variation in Gc concentration, combining both sexes, is due to electrophoretic differences between individuals (30% in females and 20% in males). Thus, the genetic component of variation in Gc concentration can be decomposed into a major gene component--the result of electrophoretic variation at the structural locus--and a second, unexplained, polygenic component.