Neospora caninum is a protozoan parasite that can cause severe disease in mammals. Two experiments were conducted to examine the effects of subcutaneous (s.c.) vaccination with Hank's balanced salt solution (HBSS), 1 x 10(5) N. caninum NC-1 strain tachyzoites or 1 x 10(5) Toxoplasma gondii TS-4 strain tachyzoites on challenge oral infections in mice with sporulated VEG strain T. gondii oocysts (1 x 10(3) oocysts exp. 1 and 5 x 10(3) oocysts exp. 2). An additional study, experiment 3, evaluated s.c. challenge with 2.5 x 10(3) tachyzoites of the highly virulent RH strain of T. gondii after vaccination with HBSS, NC-1 tachyzoites, or TS-4 tachyzoites. Mice vaccinated with NC-1 strain tachyzoites survived significantly (P < 0.05) longer than mice given HBSS in experiment 1, but not in experiments 2 and 3. Mice vaccinated with TS-4 strain tachyzoites survived significantly longer than HBSS-vaccinated mice in experiments 1, 2, and 3 and significantly longer than mice vaccinated with the NC-1 strain in experiments 2 and 3. Toxoplasma gondii tissue cyst numbers were significantly lower for mice vaccinated with TS-4 strain tachyzoites than mice vaccinated with HBSS or the NC-1 strain tachyzoites in experiment 1. No difference was observed in tissue cyst numbers in mice vaccinated with HBSS or NC-1 strain tachyzoites in experiment 1. No HBSS-vaccinated mice survived experiment 2, and the numbers of T. gondii tissue cysts were significantly lower for mice vaccinated with the TS-4 strain tachyzoites compared to NC-1 strain tachyzoites. No HBSS- or NC-1-vaccinated mice survived RH strain challenge in experiment 3. Results of these experiments indicate that infection with N. caninum provides some protection against fatal oral infection with T. gondii oocysts of a moderately pathogenic strain but not tachyzoites of a highly pathogenic strain. The protection provided bq N. caninum is much less than that provided by previous exposure to T. gondii, and the numbers of tissue cysts in the brains of mice are not significantly (P > 00.5) lowered.