Equine protozoal myeloencephalitis (EPM) is a neurologic syndrome in horses from the Americas and is usually caused by infection with the apicomplexan parasite, Sarcocystis neurona. Little is known about the role of immunobiological mediators to this parasite. Nitric oxide (NO) is important in resistance to many intracellular parasites. We, therefore, investigated the role of inducible and endothelial NO in resistance to clinical disease caused by S. neurona in mice. Groups of interferon-gamma gene knockout (IFN-gamma-KO) mice, inducible nitric oxide synthase gene knockout (iNOS-KO) mice, endothelial nitric oxide synthase gene knockout (eNOS-KO) and appropriate genetic background mice (BALB/c or C57BL/6) were orally fed sporocysts or Hanks balanced salt solution. Mice were observed for signs of clinical disease and examined at necropsy. Clinical disease and deaths occurred only in the IFN-gamma-KO mice. Microscopic lesions were seen only in the brains of IFN-gamma-KO mice. Results of this study indicate that iNOS and eNOS are not major mediators of resistance to S. neurona infections. Results of this study suggest that IFN-gamma mediated immunity to S. neurona may be mediated by non-NO-dependent mechanisms.