Background: Increased total serum IgE levels are a common characteristic of atopic disorders. Six potentially functional variants, including C-590T in the IL4 gene, C-1055T and Arg130Gln in the IL13 gene, and Ile50Val, Ser478Pro, and Gln551Arg in the IL4RA gene, have been evaluated for their involvement in the control of total serum IgE levels and related atopic disorders, but the results of these studies have been inconsistent. Objective: We examined whether these 6 variants had genotypic effects on total serum IgE levels in 823 unrelated German children from a large infant cohort, the German Multicenter Atopy Study. Methods: Marginal effect models were used for the analyses of the repeated IgE measurements. Weighted linear regression and family-based tests of association were performed to minimize the possibility of spurious effects caused by selection bias or confounding on the basis of ethnic background. Results: There are significant associations between increased total serum IgE levels and 2 variants in the IL13 gene (P < .005 and .0002 for Arg130Gln and C-1055T, respectively). These genetic effects are unlikely to be due to solely linkage disequilibrium between 2 polymorphisms, population stratification, or nonrepresentative samples. In addition, exposure to maternal smoking appears to modify the above effects on total serum IgE levels. However, no statistical association was observed between this quantitative phenotype and the other 4 variants examined. Conclusion: These findings suggest that variants C-1055T and Arg130Gln of the IL13 gene might play an important role on total serum IgE production in this study population. (J Allergy Clin Immunol 2003;112:382-8.)