A 42-year-old white man had headache, fever, chills, abdominal pain, nausea and vomiting, night sweats, and dark urine for 3 days before admission; he had history of a tick bite 6 weeks earlier. Progressive systemic deterioration, heralded by progressive hepatosplenomegaly and pancytopenia, occurred despite doxycycline therapy. Subsequent recovery was preceded by progressive resolution of hepatosplenomegaly. Progressive hepatosplenomegaly has not been previously reported in association with systemic monocytic ehrlichiosis.