A strong cell-mediated cytotoxic response (CMC), which was maximal 6-7 days after treatment, was generated in mice exposed to inactivated rabies virus vaccine. CMC response was linear and was a function of antigenic mass. Live attenuated viruses also generated a strong CMC response after intracerebral infection. Mice lethally infected with virulent strains of virus failed to develop CMC. There was, however, no difference in the rate and amount of virus-neutralizing or lytic antibodies and interferon induction in mice infected with virulent as compared to those infected with attenuated strains of virus. The level of T-cell effector function was found to be directly correlated with survival. Secondary CMC response to inactivated virus vaccine is strong, appears faster (3 days)and requires a smaller amount of antigen than does the primary CMC response. A consistent high level of CMC can be maintained for extended periods of time by repeated vaccine inoculations. When mice were treated with vaccine after being infected with street virus, high levels of CMC were found in effectively protected animals, but no CMC was found in unprotected animals. High levels of virus-neutralizing antibody were present in both surviving and dying mice. CMC responses to different antigenic components of rabies virus were also investigated.