The genetics of basal total serum IgE levels was investigated in 278 individuals from 42 randomly ascertained nuclear families. The data were analyzed using the regressive model approach to segregation analysis with age, sex, and a measure of skin test responsiveness as covariates in the Class D models. The best fitting model was that of recessive inheritance of high IgE levels with a gene frequency of 0.99 for the "high" allele. Only 3 families showed evidence for segregation of the rare "low" allele, and, if extended further, these families could be useful for molecular genetic linkage studies. These results suggest that there may be a rare allele for very low total serum IgE levels that can be detected even after a measurement of allergic responsiveness (skin test results) is considered as a covariate. Therefore, this major gene for IgE levels appears independent of any similar locus controlling atopy.