The population from five Guatemalan plantations in areas endemic for onchocerciasis was surveyed, and 1032 individuals were recruited to participate in our study. From physical examination, past clinical history (5 to 8 yr), laboratory evidence and sample availability, a group of 778 long term residents with confirmed disease status were selected for detailed examination. We were able to identify 268 long term residents of endemic areas who had never been infected, 44 of these are from hyper- and mesoendemic areas. The 44 uninfected individuals from the hyper- and mesoendemic areas, because of their considerable exposure to this disease, were classified as "putatively immune." Intact nodules containing adult worms of Onchocerca volvulus were homogenized in the presence of protease inhibitors and fractionated into particulate and aqueous isotonic soluble antigens. Systematic analysis of these Ag fractions showed considerable amounts of Ig, presumably associated with Ag in the form of immune complexes. Individual specific antibody reactions from all 778 patients to nodule Ag were examined. Reactions to O. volvulus antigens by antibodies from patients with confirmed parasitic infections were almost exclusively restricted to IgG1 and IgG4 isotypes. Antigenic activity appeared to be primarily associated with low molecular mass (14 to 29 kDa) components. Some competitive blocking of antibody activities of other isotypes by IgG1 was observed, most notable was that of IgG3 and IgA. IgG4 and IgM activities were not significantly blocked.