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Objective: To determine the clinical findings, course of treatment, and long-term outcome of horses on a farm in central Kentucky during an epizootic of equine protozoal myeloencephalitis (EPM)., Design: Cohort study., Animals: 21 horses on a farm in central Kentucky, 12 of which developed clinical signs of EPM., Procedure: Horses on the farm were serially examined for signs of neurologic disease and serum and CSF antibodies to Sarcocystis neurona. Horses were considered to have EPM if they had neurologic signs and positive test results for antibodies to S neurona in CSF. Blood values were monitored for evidence of abnormalities resulting from long-term pyrimethamine and trimethoprim-sulfamethoxazole administration Physical, neurologic, and fetal necropsy examinations were performed as needed. Horses were treated for EPM until they had negative test results for CSF antibodies to S neurona., Results: Of 21 horses on the farm, 12 had EPM over the course of 6 months. The duration of treatment ranged from 45 to 211 days, excluding 1 horse that persistently had CSF antibodies to S neurona. Adverse effects from pyrimethamine and trimethoprim-sulfamethoxazole administration included transient fever, anorexia, and depression (n = 2); acute worsening of ataxia (2); mild anemia (4); and abortions (3)., Clinical Implications: EPM may develop as an epizootic. In the horses of this report subtle clinical signs that were originally considered unimportant ultimately progressed to obvious neurologic signs. Adverse effects associated with EPM treatment included worsening of neurologic signs, anemia, abortion, and leukopenic and febrile episodes.