Monoclonal antibodies to the matrix or E1 glycoprotein of mouse hepatitis virus (MHV) were tested for their ability to protect mice from a normally lethal challenge of MHV-4. Four antibodies were tested, and two of these, J.1.3 and J.3.9, were protective. Protection did not correlate with virus neutralization in vitro, antibody isotype, recognition of a unique E1 antigenic site, or dependence on complement in vivo. Survival from acute encephalitis was followed by subacute demyelination, as has been shown with protection mediated by neutralizing monoclonal antibodies against the major glycoprotein, E2. These results demonstrate that antibodies which are specific for a viral matrix protein are able to alter the course of disease.