The mammalian reoviruses provide a model for studying specific aspects of the immunopathogenesis of viral infection. We have used two serotype 3 reoviruses to define stages in the pathogenesis of central nervous system (CNS) infection at which a mAb specific for the reoviral cell attachment protein σ1 (σ1mAbG5) acts to protect mice against lethal disease. σ1mAbG5 administered either before or at the time of footpad inoculatioin with reovirus T3D prevented entry of T3D into the CNS. σ1mAbG5 also inhibited the spread of reovirus T3C9 from the gastrointestinal tract to the CNS after peroral inoculation with T3C9. These effects occurred in the absence of a significant effect of σ1mAbG5 on primary replication in skeletal muscle (T3D) or the gastrointestinal tract (T3C9). σ1mAbG5 administered after T3D had reached the spinal cord inhibited subsequent spread of infectious virus from spinal cord to brain. Even after direct intracerebral inoculation of T3D, σ1mAbG5 prevented both growth in the brain and spread of infectious virus from brain to eye, spinal cord, and muscle. Treatment with σ1mAbG5 after intracerebral inoculation with T3D prevented neuronal necrosis and resulted in a delayed and topographically restricted inflammatory response. We detected no antibody-resistant T3D variants in vivo after treatment with σ1mAbG5. We conlcude that systemic IgG does not play a significant role at the primary site of infection with reoviruses, while it clearly acts to prevent infection of the CNS and extension of infection with the CNS. Further study will be directed to defining what components of the immune system do act at primary sites of infecton, and to defining the mechanisms by which antibody acts at defined stages in pathogenesis.