SummaryBackground A gain of function mutation (Q551‐ > R) in the IL‐4 receptor α‐chain (IL‐4Rα) has been found to be associated with atopy in some studies but not others. The different results may be explained by interactions between the IL‐4Rα polymorphism and environmental factors.Objectives To identify interactions between the R551 mutation and environmental factors that are associated with atopy.Methods DNA from the Children in Focus (CiF) cohort of the Avon Longitudinal Study of Parents and Children (ALSPAC) was genotyped by heteroduplex formation for the presence of the R551 polymorphism. The data were then analysed for associations with flexural eczema as an indicator of atopic eczema, skin prick tests to allergens and serum IgE levels, and for interactions with environmental factors.Results A significant (P = 0.02) positive association was seen between the R551 polymorphism and flexural eczema in children up to 6 months of age who had not been given antibiotics, but not in children who had been given antibiotics. This association was maintained as a trend until 30 to 42 months of age but was no longer statistically significant. There was no significant association between the R551 polymorphism and positive skin prick tests or levels of serum IgE at 61 months of age, consistent with the effect of the R551 polymorphism being restricted to early life.Conclusion There is an association between the R551 polymorphism and flexural eczema in children at 6 months of age who have not had infection requiring treatment with antibiotics. Restriction of the R551 association with eczema to children who have not had antibiotics lends support to the ‘hygiene hypothesis’, which states that exposure to infection in childhood can protect against allergic disease.