Despite the detection ofNeorickettsiaspecies DNA sequences in various trematode species and their hosts, only threeNeorickettsiaspecies have been cell culture isolated and whole-genome sequenced and are known to infect mammals and/or cause disease. The molecular mechanisms that enable the obligatory intracellular bacteriumNeorickettsiato colonize trematodes and to horizontally transmit from trematodes to mammals, as well as the virulence factors associated with specific mammalian hosts, are unknown. Potomac horse fever (PHF) is a severe and acute systemic infectious disease of horses, with clinical signs that include diarrhea.Neorickettsia risticiiis the only known bacterial species that causes PHF. Ingestion of insects harboringN. risticii-infected trematodes by horses leads to PHF. Our discovery of a newNeorickettsiaspecies that causes PHF and whole-genome sequence analysis of this bacterium will improve laboratory diagnosis and vaccine development for PHF and will contribute to our understanding ofNeorickettsiaecology, pathogenesis, and biology.