Background: Both genetic and environmental factors, e.g. early childhood infections, have a role in the pathogenesis of atopic diseases. Objective: To examine simultaneously the strength and possible interactions of two known such factors, IL4 genetics and Helicobacter pylori infection, on the risk of atopy and asthma. Methods: Gene polymorphism analyses and skin prick tests (SPT) were determinedin 245 adult asthmatics and 405 nonasthmatic controls of population-based case-control study. SPTs were used as an indicator of atopy. H. pylori infection was verified by detecting anti-H. pylori IgG antibodies in sera. Results: A significant negative association was seen between the presence H. pylori antibodies and SPT positivity (≧1 positive reactions) in both asthmatics and controls (p = 0.002 and p = 0.025, respectively) but the effect of IL-4 polymorphism (SNP –590C/T) was nonsignificant in both groups (p = 0.071 and p = 0.072, respectively). However, IL4 genetics had an effect on susceptibility to H. pylori: asthmatics carrying the IL4 –590 allele T had a diminished risk to be H. pylori infected (OR 0.485 95%CI 0.287–0.819). This effect was not seen in controls. Logistic regression analysis indicated that H. pylori and IL4 effects on atopy risk are not interdependent. Conclusions: This study showed that the effect of H. pylori infection on atopy risk is stronger than that of IL4 genetics. There is no interaction between these factors on the pathogenesis of atopy suggesting that these factors have distinct immunopathogenetic mechanisms. However, the genetic effect may modify the role of infective agents by effecting on susceptibility to disease.