Lymphocyte transformation (LT) responses to coccidioidin (CDN) and spherulin were suppressed in 11 (73%) of 15 patients with active coccidioidomycosis when their mononuclear cells were assayed in autologous serum as compared to serum from healthy, CDN skin test-positive subjects. Suppressed LT responses were specific for Coccidioides immitis antigens in 7 (64%) of the 11 patients. Immunoaffinity chromatography of patient sera with Staphylococcus protein A adsorbed the suppressor component(s) and thereby established that suppression was attributed to immunoglobulin G, either alone or complexed with antigen. The possibility that suppression was mediated by immune complexes was examined by adding complexes formed in vivo or in vitro to mononuclear cell cultures of healthy CDN-reactive persons before LT assays. Although complexes prepared in this manner were reactive in an enzyme-linked immunosorbent assay designed to detect Coccidioides antigen-specific immune complexes, no suppression of LT responses was observed. We conclude that serum-mediated suppression of LT responses in coccidioidomycosis is attributed to monomeric and not immune-complexed immunoglobulin G antibody.