Equine protozoal myeloencephalitis (EPM) is a neurologic syndrome seen in horses from the Americas and is mainly caused by Sarcocystis neurona. Cell-mediated immune responses to mitogens have been shown to be reduced in horses with EPM, although it is not known whether the parasite causes this immunosuppression or if the immunosuppression is required for disease manifestation. Recently, a 29-kDa surface antigen from S. neurona merozoites was identified as being highly immunodominant on Western blot. This antigen has been sequenced and cloned, and the expressed protein has been named SnSAG1. Isolated peripheral blood lymphocytes from 43 EPM-negative horses and 28 horses with clinical EPM were cocultured with a mitogen or SnSAG1, and lymphocyte blastogenic responses to these antigens was measured by tritiated thymidine uptake. The ability of SnSAG1 to induce γ-interferon (γIFN) production was also investigated with reverse transcriptase–polymerase chain reaction. There was no significant differences between EPM-positive and -negative horses in lymphocyte responses to ConcanavalinA. However, lymphocytes from EPM-negative horses responded significantly higher to SnSAG1 than lymphocytes from EPM-positive horses. γIFN production was detectable by 24 hr in culture in response to SnSAG1 in all EPM-negative horses. There was still no detectable γIFN production in EPM-positive horses after 72 hr in culture. It appears that the parasite is also able to induce an immunosuppression toward parasite-derived antigens as parasite-specific responses are decreased.