Genetic studies of IgE-mediated atopic disease have produced conflicting results, due largely to variable phenotype definitions. Total IgE concentrations and 14 allergen skin prick tests (SPT) were determined in 1099 members of families with history of atopy. Log10 [Total IgE] values were normally distributed in both atopic (SPT [+]) and non-atopic (SPT [-]) groups. The mean Log10 [Total IgE] value was higher in the atopic group, although the standard deviations of the distributions were the same. The mean Log10 [Total IgE] value of the non-atopic distribution was subtracted from the individual Log10 [Total IgE] values of the atopic group giving an allergen-specific fraction. There was a strong positive correlation between the specific IgE fraction and the number (#) SPT [+] results, defined as Cognate IgE. Among the atopics, subtracting the Cognate IgE value from total IgE yielded Non-Cognate IgE. The Cognate and Non-Cognate IgE distributions were statistically uncorrelated. Evidence is presented for two serum IgE fractions that are statistically and physiologically independent of one another in atopic families; a Cognate IgE fraction associated with atopic sensitization and a Non-Cognate IgE fraction unrelated to atopic disease. Elevated serum IgE is a consequence, not a predisposing cause, of allergen sensitization.