Immunological cross-reactivity between environmental allergens and helminth proteins has been demonstrated, although the clinically related implications of this cross-reactivity have not been addressed. To investigate the impact of molecular similarity among allergens and cross-reactive homologous helminth proteins in IgE-based serologic assessment of allergic disorders in a helminth-infected population, we performed ImmunoCAP tests in filarial-infected and noninfected individuals for IgE measurements to allergen extracts that contained proteins with high levels of homology with helminth proteins as well as IgE against representative recombinant allergens with and without helminth homologs. The impact of helminth infection on the levels and function of the IgE to these specific homologous and nonhomologous allergens was corroborated in an animal model. We found that having a tissue-invasive filarial infection increased the serological prevalence of ImmunoCAP-identified IgE directed against house dust mite and cockroach, but not against timothy grass, the latter with few allergens with homologs in helminth infection. IgE ELISA confirmed that filaria-infected individuals had higher IgE prevalences to those recombinant allergens that had homologs in helminths. Mice infected with the helminth Heligmosomoides polygyrus displayed increased levels of IgE and positive skin tests to allergens with homologs in the parasite. These results show that cross-reactivity among allergens and helminth proteins can have practical implications, altering serologic approaches to allergen testing and bringing a new perspective to the "hygiene hypothesis."