SummaryBackground Hayfever is determined by an interaction of environmental and genetic factors and biologically characterized by an imbalanced T helper cell 1 (Th1) and Th2 immune response and elevated IgE levels against inhalant allergens. Indications exist that polymorphisms in cytokine genes involved in the regulation of the Th1/Th2 balance may contribute to the allergic phenotype.Objective We investigate whether polymorphisms in genes directly or indirectly involved in Th1, Th2 immune response are associated with hayfever and elevated IgE levels against inhalant allergens.Methods From a subsample of the European Prospective Investigation into Cancer and Nutrition‐Heidelberg, 322 subjects with hayfever and 322 age‐ and sex‐matched non‐allergic controls were selected and genotypes determined for 15 polymorphisms in 13 genes. Plasma IgE against inhalant allergens was measured via CAPSX1 (Phadiatop) test. We computed odds ratios (ORs) by logistic regression, tests on group differences of IgE‐levels in dependence upon genotype and tests for trend by means of non‐parametric methods.Results We found decreased OR for hayfever (OR=0.60, 95%CI=0.4–0.9) and sensitization to inhalant antigens (OR=0.5, 95%CI=0.4–0.8) in heterozygotes of the IL‐6 −174 G/C polymorphism. Homozygotes of the G‐allele in IL‐2 −330 T/G were at increased risk of hayfever (OR=2.6, 95%CI=1.3–5.2). Moreover, we found indications for differences in IgE levels against inhalant allergens in dependence upon genotypes of polymorphisms in IL‐4R, IL‐6, IL‐13, and IL‐18.Conclusion Our data suggest an association of genetic variants in IL‐6 and IL‐2 with hayfever, confirm a role of polymorphisms in IL‐4R, IL‐13, and IL‐18 for the elevated IgE phenotype, and add IL‐6 to the list of candidate genes.