Specific immunoglobulin E (IgE) responses are upregulated during chronic schistosome infection and during allergy. These responses are tightly regulated during schistosomiasis. We have previously shown that IgE regulation depends on the extent and length of exposure to individual parasite allergen-like proteins. Here we compare the development of IgE and immunoglobulin G4 (IgG(4)) responses to the differentially expressed allergen-like proteins SmTAL1 and SmTAL2 among preschool-aged children from 2 villages with different levels of Schistosoma mansoni transmission. We found a lack of SmTAL1 responsiveness among all children, but evidence for IgG(4)-dependent IgE-SmTAL2 desensitization in both villages, occurring earlier among children from the village where the level of transmission was greater. Findings provide insights into the development and regulation of allergic-type immune responses.