A syncytium-inducing reovirus was recently isolated from brain homogenates of a baboon suffering from acute, progressive meningoencephalo myelitis. This baboon reovirus (BRV) was classified as a member of the genus Orthoreovirus, family Reoviridae, on the basis of the characteristic capsid morphology and genome and protein profiles. We have assessed the relationship between BRV and the other syncytium-inducing reoviruses in order to determine whether the emergence of this virus represents a host range or pathogenic alteration in a previously described isolate or the appearance of a novel entity. BRV was compared to representative members of the prototype mammalian reoviruses, avian reoviruses, and Nelson Bay virus on the basis of electropherotype, protein profile, and antigenic similarity as measured by immunoprecipitation using homologous and heterologous antisera. In spite of similarities between the genome and protein profiles of BRV and the other orthoreoviruses, migration-rate polymorphisms indicate that BRV has diverged extensively from the previously described syncytium-inducing orthoreoviruses. Most importantly, the limited epitope conservation suggests that BRV has existed in genetic isolation from other reoviruses for quite some time. We conclude that BRV represents a novel syncytium-inducing mammalian reovirus, which is of particular interest in view of its association with disease in nonhuman primates during natural infections and its unusual syncytial phenotype.