Viruses are associated with the development of autoantibody-mediated blood autoimmune diseases. A two-step mechanism could explain virus involvement in the development of experimental hemolytic anemia. Immunization of normal mice with rat erythrocytes results in an autoantibody production that could be enhanced by viral infection, without erythrocyte destruction. Inoculation of the same virus when autoantibodies are at high levels triggers clinical anemia. This results from macrophage activation by gamma-interferon, leading to exacerbated erythrophagocytosis. Thus the development of anemia during the course of viral infection may require two independent stimuli, in which the first triggers autoantibody production and the second enhances the pathogenicity of these autoantibodies.