Neospora caninum is a coccidial protozoan parasite that appears morphologically indistinguishable from Toxoplasma gondii and that infects a large range of mammals. Both inbred and outbred strains of mice exhibit a high degree of resistance to infection with N. caninum. Three inbred strains of mice (A/J, BALB/c, and C57BL/6) that were infected intraperitoneally with N. caninum were protected against a lethal challenge from T. gondii. Vaccine-induced protection was Neospora dose dependent. A rise in the CD8⁺ T-cell population in mice that had been vaccinated with N. caninum and challenged with T. gondii was observed. Adoptive transfer of CD8⁺ T-cell splenocytes from N. caninum-infected mice was protective against challenge with Toxoplasma. The CD8⁺ T cells from Neospora-infected mice proliferate to both Neospora and Toxoplasma antigens in vitro and secrete substantial quantities of gamma interferon when pulsed with the parasite antigen. These observations demonstrate that N. caninum protects against lethal T. gondii infection by the induction of CD8⁺ T cells that are immunoreactive to both parasites.