Ehrlichia chaffeensis causes human monocytic ehrlichiosis (HME) that usually includes fever, myalgias, and pancytopenia and, in 80% to 90% of patients, elevations in serum transaminase levels. Thus, the pathology of liver injury was studied in liver tissues from 7 patients with laboratory-confirmed HME. H&E and immunohistochemical stains for E chaffeensis and leukocyte markers were examined. Scattered lobular lymphohistiocytic foci and diffuse lymphohistiocytic infiltration and Kupffer cell hyperplasia with increased phagocytosis frequently were present. Various degrees of liver cell injury and death were observed. Cholestasis was evident in 6 cases, sometimes with bile duct epithelial injury. Rare to abundant E chaffeensis-infected mononuclear cells infiltrating lobules or portal regions or in Kupffer cells were observed in 5 patients. The inflammation was out of proportion to the infection in 6 cases. In the absence of infected hepatocytes or biliary epithelial cells, these findings suggest that host inflammatory or immune responses contribute to the liver injury seen in HME.