Previous studies of human granulocytic ehrlichiosis (HGE) suggest a role for host immune response in resolving infection and in causing histopathological lesions. We hypothesize that interferon (IFN)-gamma allows tissue injury that is suppressed by interleukin (IL)-10 after initiation by ehrlichia infection. Thus, parental C57BL/6, IL-10-/-, and IFN-gamma-/- strains of mice were infected and then assayed for hepatic histopathological lesions, ehrlichial burden, and cytokine responses to ehrlichial antigen in primary splenic cultures during the first 21 days after infection. Histopathological severity in C57/BL6 and IL-10-/- mice rose in parallel through day 7, but then diverged as pathology in IL-10-/- mice continued to increase and remained high throughout the course of the study. The histopathological rank of C57BL/6 of mice decreased at day 10 and returned to baseline levels at days 14 and 21. In contrast, the IFN-gamma-/- strain had baseline pathology scores throughout the course of the infection, yet had significantly higher ehrlichial burden both in the blood and tissues than C57BL/6 or IL-10-/- mice. This suggests that histopathological lesions in the HGE murine model do not result from direct ehrlichia-mediated injury but from immunopathological mechanisms initiated by ehrlichial infection. The similarities with lesions in humans suggest an immunopathological basis for HGE.