The development of autoimmunity in New Zealand mice is related to genetic, immunologic, and viral factors. Evidence is presented to suggest that thymus-dependent immune functions may be depressed and bone marrow-dependent functions augmented in these mice. Antibodies to RNA and DNA appear spontaneously and can also be induced by treatment with rI·rC. Antibodies binding rI·rC-14C in human lupus sera, in NZB/NZW F1 (B/W) mice developing lupus, and in NZB, ALN, and ALN/NZB mice have greatest specificity for reovirus double-stranded RNA. Treatment of B/W mice with RNA and cyclophosphamide induces immunologic tolerance, and suppresses antibodies binding rI·rC-14C. During recovery, the specificity of the antibodies is unaltered. Induction of tolerance in this way prevents the accelerated formation of anti-RNA antibodies normally induced by MLV. This finding suggests that virus-accelerated and natural disease occur through a similar mechanism, and supports the hypothesis that viruses may act as antigenic stimuli for a genetically hyper-responsive antibody-producing system.