The immune response to the nominal phosphoprotein (NS protein) of rabies virus was investigated with the use of a vaccinia recombinant virus that expressed the NS protein of a fixed rabies virus strain. Mice of the H-2k haplotype that were injected with either live rabies virus or the vaccinia recombinant virus developed a strong cytolytic T-cell response specific for the NS protein. This response was under immune response (Ir) gene control. The NS protein as presented by the vaccinia recombinant virus was a poor inducer of rabies virus-specific T-helper (Th) cells and B cells in the H-2k background. Furthermore, mice of the H-2k haplotype could not be protected by vaccination with the vaccinia recombinant virus expressing the NS protein, although protection in outbred mice was partial and incomplete. These data indicate that cytolytic T cells to the NS protein of rabies virus are insufficient to protect mice against a challenge with rabies virus.