Cattle experimentally infected with Onchocerca lienalis were examined by enzyme-linked immunosorbent assay and immunoblotting to determine the degree of stage- and species-specificity in the immune response to infection. Levels of serum antibodies to antigens derived from third-stage larvae increased little after the first three weeks of infection, and the range of antibody specificities remained limited following the appearance of microfilariae (mf) in the skin. In contrast, antibodies to antigens from adult worms of either sex exhibited a vigorous response, characterized by a series of peaks arising 15–30, 79, and > 266 days after infection that were coincident with the timings of larval molts and the onset of a patent infection. Antibody specificities to the adult worms included many directed to molecules that were shared with other life-cycle stages, but some were stage-specific and others were confined to one sex. A response cross-reactive with antigens from mf was initiated during the prepatent period, but antibody levels increased steeply after the infection became patent. This was followed by a major expansion of antibody specificities to products exclusively directed to mf, most notably in the range of 12–18 kilodaltons. Sera from O. lienalis-infected cattle cross-reacted extensively with antigens derived from O. volvulus adult worms and the profiles of antibody levels over time were indistinguishable from those obtained with O. lienalis extracts. The dominant response was of IgG1, although limited IgG2 and IgM reactivities were found, while no Onchocerca-specific IgA was detected. These results demonstrate that parasite development has a profound influence on the level and repertoire of antibodies produced during Onchocerca infections, and that extensive cross-reactivity exists between O. lienalis and O. volvulus, lending support to the role of cattle models in the study of human onchocerciasis.