To compare clinical features and assess risk factors for human granulocytic ehrlichiosis (HGE) and early Lyme disease, we enrolled patients in a case-control study during the 1996 and 1997 tick seasons. Clinical and demographic characteristics were assessed for patients with laboratory-confirmed cases of HGE or Lyme disease, and risk factors were compared with those of matched control subjects. We identified 83 persons with Lyme disease, 27 with HGE, and 11 with apparent coinfection. Unsuspected Ehrlichia infection was identified in 8 (13%) of 60 patients with Lyme disease. Patients with HGE were older and more likely to have fever, chills, or dyspnea than were those with Lyme disease only. Most patients with apparent coinfection did not have hematologic abnormalities. In the risk factor analysis, tickborne illness was independently associated with rural residence and camping. The clinical spectrum of HGE overlaps that of Lyme disease, and physicians in areas of endemicity should consider both diseases in treating patients with a compatible rash or febrile illness.