The Ehrlichia phagocytophila-group also includes E. equi and the human granulocytic ehrlichiosis (HGE) agent that are probably a single species. Disease is mild to severe illness in ruminants, horses, and humans, but the comparative pathology and ehrlichial distribution in tissues is poorly described. We compared pathology and ehrlichial distribution in humans with HGE, horses with E. equi infection, and a sheep with E. phagocytophila infection. Frequent findings included splenic lymphoid depletion, small macrophage aggregates and apoptoses in liver, and paracortical hyperplasia in lymph nodes. Bone marrow was normocellular or hypercellular. Only the spleen was frequently infected; other organs with infected cells included lung, liver, heart, and kidney, but lesions were present in lung and liver only. Most infected cells were neutrophils. Ehrlichia phagocytophila-group infections are associated with moderate tissue damage. While the pathogenesis of granulocytic ehrlichiosis is not clear, pathologic studies suggest that the process is initiated by ehrlichia-infected cells but may result from host-mediated injury and immunosuppression.