Diffuse cutaneous leishmaniasis is characterized by multiple nonulcerative skin lesions. Histologically, these lesions are dominated by vacuolated, heavily infected macrophages, with only a few lymphocytes present. A unique focus of diffuse cutaneous leishmaniasis is present in the Dominican Republic. We studied four patients with this disease. None had a delayed reaction to leishmanial antigen on skin tests. The total numbers of lymphocytes and T cells were normal. None of these patients had a lymphocyte-proliferation response to leishmanial antigens, although their responses to other antigens were normal. Adding indomethacin to cultures or decreasing the number of adherent cells by passage of cells over nylon wool reconstituted the lymphocyte responses to leishmanial antigens. Thus, our studies demonstrate that patients with diffuse cutaneous leishmaniasis have a selective anergy to leishmanial antigen, and that an adherent suppressor cell is one mechanism by which this selective immunosuppressive state is modulated.