With the emergence of raccoons (Procyon lotor) as the primary rabies reservoir in the United States of America, a recombinant vaccinia-rabies glycoprotein (V-RG) virus vaccine was developed that protected raccoons by the oral route from rabies infection. Despite extensive laboratory evaluation, vaccine safety concerns remained about free-choice distribution for wildlife rabies control. In this study, the oral innocuity of V-RG virus was demonstrated in immunodeficient mice but parenteral exposure resulted in systemic and progressive infection, albeit significantly abrogated in severity in comparison to vaccinia virus. Treatment with vaccinia immune globulin and hydroxyphosphonylmethoxy-propyl-cytosine resulted in significantly longer survival and minimized V-RG viral gross lesions.