Salem virus (SalV) is a recently identified equine virus belonging to the family Paramyxoviridae. The only known isolate was obtained from a horse that was involved in a disease outbreak of undetermined nature and the circumstances of its isolation suggested an etiologic role. However, the experimental infection of a colostrum-deprived foal failed to reproduce the disease; only mild neutropenia and temperature elevation were recorded. An additional attempt to establish an etiological relationship with the disease was made by conducting a retrospective evaluation of the serological profiles of animals involved in the outbreak. Animals reported as being affected by the disease according to a comprehensive United States Department of Agriculture (USDA) database were found to be 48% (n=27) positive for antibodies to SalV, but the percent positive for all horses, affected and unaffected, was actually higher at 56% (n=62). For 15 affected horses for which paired acute and convalescent serum specimens were available, no unequivocal seroconversions to SalV were identified. Furthermore, the horse from which SalV was isolated was not listed as one of the animals affected by the disease. In total, the evidence suggests that SalV was not the etiological agent of the disease and that its isolation was fortuitous.