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The serum antibody responses (specific IgG1, IgG4, and IgE, and total IgE) to Dracunculus medinensis infection in humans from a highly endemic area of northern Ghana were examined regularly by ELISA over a period of one year in cohorts of individuals who developed a patent D. medinensis infection during the study period (actively infected category), or who claimed to have never had a patent infection (endemic normal category). The results were analyzed in relation to seasonality and time of patency of infection. For individuals in the actively infected category, a clear seasonal variation in the mean levels of specific IgG1 and IgG4 was found, with the highest levels late in the dry season and early in the rainy season, when transmission is high, and the lowest levels late in the rainy season and early in the dry season. Endemic normal individuals responded with low and fluctuating levels of specific IgG1 and with low and nonfluctuating levels of specific IgG4. For specific and total IgE, no seasonal variation was observed in any of the two infection status categories. In relation to time of patency of infection (only involving the category of actively infected individuals), the mean levels of specific IgG1 and IgG4 increased from two months before patency of infection, peaked during patency, and then gradually decreased for four months until a constant level was reached. No significant fluctuations in the levels of specific and total IgE were observed in relation to time of patency. The present study thus showed extensive variation in levels of D. medinensis-specific IgG1 and IgG4 (but not IgE) over time. Seasonal variations in antibody responses may also occur in other helminth infections, especially those with seasonal transmission, and these should be taken into consideration when interpreting the results of immunologic studies.