To evaluate pathology and the role of immune status in a murine model system of human granulocytic ehrlichiosis (HGE), C3H/HeJ, C3H-SCID, and Peromyscus leucopus mice were infected with an HGE agent. All mice remained healthy. Ehrlichemia was not detected after day 14 in P. leucopus and C3H/HeJ mice but increased between days 14 and 90 in C3H-SCID mice. In tissues examined at day 21 and later, infection was rarely detected in immunocompetent mice but was present in all C3H-SCID mice and included pulmonary endothelialitis and hepatic mononuclear cell aggregates with apoptoses. HGE agent was demonstrated in mature and immature myeloid cells in hematopoietic tissues and infrequently in lung and liver lesions with deposition of infected cells. HGE agent infection in immunocompromised mice progresses slowly, has a higher infectious burden and more tissue pathology and is persistent. A murine model for HGE may be useful to assess pathologic lesions, transmission, and persistence.