Equine motor neuron disease (EMND), a newly described neurodegenerative disease, bears a striking resemblance to progressive muscular atrophy (PMA) in humans. We present a comparison of the equine and human diseases and the results of a case-control study conducted to identify intrinsic factors associated with EMND. Cases included all horses with a confirmed diagnosis of EMND diagnosed in the United States since 1985 (32 cases). Controls included horses diagnosed with either cervical stenotic myelopathy, equine degenerative myeloencephalopathy, or protozoan myelitis at the Veterinary Teaching Hospital at the College of Veterinary Medicine, Cornell University (153 controls). Logistic regression analysis identified factors associated with the risk of EMND. Risk factors considered were age, sex, and breed of the horse. Most cases of EMND (30 of 32) have been sporadic. There was a breed association with the risk of EMND. Quarter horses were at a high risk for developing EMND (odds ratio [OR] = 12.7; 95% confidence interval, 3.3 to 49.6); thoroughbred horses were at increased risk (OR = 2.9, 0.8 to 10.4). There was also an age association with the risk of EMND. The risk increased with age, peaked at 16 years, and then declined, a pattern similar to that for amyotrophic lateral sclerosis in humans. There was no sex association with the disease. Despite the breed association, equine lymphocyte antigen studies have not revealed a systematic pattern, suggesting that genetic factors influencing susceptibility to EMND may be outside the major histocompatibility complex.