Natural antibodies to gamma interferon (IFN-gamma) were found in patients suffering from different viral diseases and, at a lower titer, in healthy individuals. Such antibodies were affinity-purified and studied for their capability to interfere in vitro with the antiviral and immunomodulating activity of IFN-gamma. Data obtained show that these human anti-IFN-gamma antibodies have no inhibitory effect on the antiviral activity of IFN-gamma. On the contrary, they are able to inhibit the expression of Fc receptor sites and HLA-DR antigens induced by IFN-gamma on the U-937 cells, a human monocytoid/macrophage-derived cell line. These antibodies can also interfere in a mixed lymphocyte culture (MLC) with the proliferation of lymphocytes and the generation of cytotoxic lymphocytes. However, they showed only a moderate inhibitory effect on the cytotoxicity generated in MLC to K-562 cells. Human antibodies capable of interfering with the immunomodulating activities of IFN-gamma might open up a new field in clinical therapy for those diseases that carry evidence of activated cell-mediated immunity.