<i>Background:</i> Asthma and rhinitis may represent two manifestations of the same airway disease. Genetic research can increase our understanding of their common or distinct pathogenesis. <i>IL13</i> and <i>IL4R</i> polymorphisms are associated with asthma and show gene-gene interaction in asthma. Their role in rhinitis has not been extensively studied. <i>Methods:</i> Association of <i>IL13</i> and <i>IL4R</i> polymorphisms in relation to rhinitis, asthma, serum IgE and skin test response was studied in: (1) 188 trios ascertained through a proband with rhinitis who were clinically not affected by asthma; (2) 407 trios with an asthmatic proband, and (3) 118 asthma cases and 102 unrelated healthy controls using family-based association testing, logistic regression, and analysis of variance as appropriate. Gene-gene interaction was evaluated using logistic regression analysis. <i>Results: </i><i>IL13 </i>C–1111T (rs1800925) was significantly associated with rhinitis and atopic phenotypes in rhinitis trios that were not affected by clinical asthma. <i>IL13 </i>Arg130Gln (rs20541) and G870A (rs1295685) were consistently associated with asthma and serum IgE in both asthma populations. <i>IL4R </i>Glu375Ala (rs1805011) and Ser411Leu (rs1805013) were associated with asthma in the asthma case-control population. Combining risk genotypes of <i>IL13 </i>Arg130Gln with <i>IL4R </i>Glu375Ala, and<i> IL13 </i>C–1111T with <i>IL4R </i>Ser478Pro yielded increased risks for asthma compared to their separate effects. <i>Conclusion:</i><i>IL13 </i>polymorphisms were associated with asthma and rhinitis without clinical asthma; thus, these polymorphisms may constitute a common etiologic pathway for their development. In addition, the study replicates a previously reported interaction of <i>IL13</i> and <i>IL4R </i>polymorphisms in asthma.