The natural incidence of antinuclear factor (ANF) has been examined in several mouse strains using a standard fluorescent anti-globulin technique. NZB mice with autoimmune disease had an ANF incidence of about 40%, whereas the normal strains C3H and C57/Bl showed delayed onset of about 15% incidence. F1 (NZB × C3H) showed a distinctive sex difference, females eventually showing about the NZB incidence and males the C3H incidence. The apparently normal Hall Institute “outbred” mice showed a steady increase to an ANF incidence of about 85%. The murine ANF appeared to be all or mainly a 7 S γ-globulin with nucleoprotein specificity. In NZB mice, an increased ANF incidence was associated with severe renal disease, early splenectomy in males, partial or complete thymectomy, and receipt of a thymus graft, whereas a decreased ANF incidence was associated with late splenectomy in females.