The specific serum IgG1, IgG4, and IgE responses to Dracunculus medinensis and the level of total IgE of individuals living in a highly endemic area of northern Ghana were measured by ELISA. Sera were obtained in the high transmission season from individuals with prepatent, patent, or postpatent infection as well as from individuals from the same endemic area who claimed to have never had a patent infection (i.e., endemic normal individuals). Individuals with prepatent or postpatent infections responded with a significantly lower mean level of specific IgG1 and IgG4 compared with individuals with a patent infection, and with a significantly higher mean level of specific IgG1 and IgG4 compared with endemic normal individuals. For specific IgE, no differences were found in the mean antibody level between the infection status categories. Individuals with a patent infection had a significantly lower mean serum level of total IgE compared with prepatent, postpatent, and endemic normal individuals. Endemic normal individuals had the highest mean level of total IgE. Furthermore, in all clinical categories, high responders for specific IgG1 and IgG4 generally had low levels of total IgE, whereas low responders for specific IgG1 and IgG4 generally had high levels of total IgE. A similar dichotomy, although less distinct, was observed between specific IgG1 and IgG4 on the one hand and specific IgE on the other. Thus, similar to what has been suggested for schistosomiasis and lymphatic filariasis, the relationship between the IgG subclasses and IgE appears to play a role in, or at least to reflect, a mechanism for protective immunity in dracunculiasis.