Human Th2 cytokines (interleukins 4 and 13) induce co-expression of IgE and IgG4 through sequential switching. The regulation of IgG4 responses and the role of these responses in the pathogenesis of allergy have not been characterized. We are addressing these issues by comparing and contrasting the expression of allergen-specific IgE and IgG4 in a population of European children thoroughly defined for lifestyle, environmental exposures and allergic phenotypes. The current analysis focused exclusively on children from non-farming families (n=493) in order to avoid potential effects of exposure to microbial products abundant in farming environments. We found that allergens induce Th2-mediated IgG4 and/or IgE responses in the majority of the population. Approximately two-thirds of the children had allergen-specific IgG4 but not IgE, only a minority had both IgG4 and IgE, only a few were negative for both, and virtually none had only IgE. The prevalence of asthma and hay fever was dramatically higher in children with high IgG4 and IgE compared to children who only mounted IgG4 or low IgG4 and IgE responses. These results appear to recapitulate different stages of in vivo Th2-dependent sequential switching from IgG4 to IgE. These patterns of Th2-induced antibody responses may warrant a redefinition of the notion of allergen sensitization.