Although persistent infection of animals by members of the genus Ehrlichia is well known and may be associated with subsequent severe or fatal illness, persistent infection of humans with Ehrlichia chaffeensis has not been reported. Herein we report a typical case of serologically documented acute ehrlichiosis; despite therapy with tetracycline and chloramphenicol, the patient's condition progressively worsened and he suffered multiple secondary infections and gastrointestinal hemorrhage. He died 68 days after his initial hospitalization. Retrospective immunohistologic examination of both acute-phase bone marrow specimens (obtained day 12 of illness) and postmortem liver tissue specimens (obtained day 68 after onset of disease) revealed E. chaffeensis morulae in mononuclear cells, presumably macrophages and monocytes. Findings of this case provide the first definitive evidence that E. chaffeensis is capable of establishing persistent human infection and suggest a role for this obligate intracellular bacterium in the induction of immune compromise associated with a fatal outcome.