A longitudinal study was carried out in Madagascar, the most important focus of chromoblastomycosis (P. Esterre, A. Andriantsimahavandy, E. Ramarcel, and J. L. Pecarrere, Am. J. Trop. Med. Hyg. 55:45-47, 1996), to investigate natural immunity to this disease. Sequential blood samples were obtained before, during, and at the end of a successful therapeutic trial with terbinafine, a new antifungal drug. Using enzyme-linked immunosorbent assay and immunoblot methods, detailed analyses of antibody concentration and antigen mapping were conducted for 136 serum samples and tentatively correlated to epidemiological and pathobiological data. Two different cytoplasmic antigens, corresponding to the two fungal species involved (Fonsecaea pedrosoi and Cladophialophora carrionii), were used to analyze the distribution of different classes of immunoglobulins. This was done with respect to the origin of the isolates, clinical and pathobiological. Although strong individual variations were noticed, some major antigens (one of 18.5 kDa specific for F. pedrosoi and two of 23.5 and 33 kDa, respectively, specific for C. carrionii) corresponded to high antibody prevalence and concentration. As some antigenic components were also detected by immunoglobulin M (IgM) and IgA antibodies, the role that these specific antibodies could play in the immune response is discussed.