Considerable evidence is available suggesting a significant genetic component in the pathogenesis of asthma, but the mechanism of inheritance is not well understood. The main objective of this study was to assess if total serum IgE level, a known intermediate phenotype for asthma, is under the control of a major autosomal gene. We studied nuclear families participating in the Tucson Children's Respiratory Study in Tucson and originally selected because they belonged to a health maintenance organization. One hundred twenty-five Hispanic and 673 non-Hispanic White nuclear families were eligible; 50 Hispanic families (with 191 subjects) and 241 non-Hispanic White families (with 886 subjects) were included. Prevalence of asthma, hay fever, and parental smoking was similar among eligible families who were included and those who were not. Segregation analyses using regressive models for continuous traits showed that the best fit to the data was given by a model of Mendelian codominant inheritance of a major autosomal gene associated with higher serum IgE level. Log-likelihood for this model was not significantly different from that of the best-fitting ("unrestricted") model (P = .3) and was significantly better than log-likelihood for a dominant model (P < .0001) and a recessive model (P < .0001). An environmental model showed significant departure (P < .0001) from the unrestricted model. Tests for genetic heterogeneity showed no significant difference between the two ethnic groups. The data strongly suggest that total serum IgE levels are controlled by a major autosomal codominant gene.