Objective of the investigation was to model the adverse action of vaccinia virus (VV), caused by oral immunization of mice and to evaluate efficacy of its reduction, using therapeutic and prophylactic drugs. Materials and methods. Virological and immunological research methods were used. Results and conclusions. Reproduced was pathological action of VV in the orally infected mice. The ability to reduce the side effect and protect mice from lethal infection was demonstrated by such preparations as Metisazon, Likopid, and NIOCH-14 orally administered in the investigated schemes. Moreover preliminary single oral immunization with TEOVak smallpox vaccine before oral infection with Neurovaccine-92 strain of VV also lowered pathogenic effect and protected mice against death. All the investigated schemes of drug administration did not affect the immune response if used alongside with TEOVak smallpox vaccine and can be deployed to develop safe schemes of primary oral vaccination against smallpox. In addition, such drugs as Ribomunil, Immudon, Ingavirin can be used as means to enhance the immune response to smallpox vaccines.