New Zealand Black (NZB) mice develop a disease complex which resembles autoimmunity in man. Cells from both NZB embryos and adults spontaneously produce an infectious C-type virus which is xenotropic (X-tropic)-capable of being passed only to cells foreign to the host species. It differs from other endogenous murine C-type viruses which are ecotropic, i.e. infectious for cells of their home species. Xenotropic viruses are detected in embryos and adult tissues of other strains of mice but at less frequency and titer than in NZB mice. Moreover, natural anti-X-tropic virus neutralizing activity which is present in all mouse sera, is found in significantly higher titers in NZB mouse sera. A working hypothesis is that the X-tropic virus is an important agent for normal development and differentiation, but in NZB mice its increased expression results in autoimmune disease. Furthermore, its interaction with endogenous ecotropic virus leads to phenotypic mixing with possible enhancement of the immunologic disorders.