Babesiosis is a malaria-like, tick-transmitted zoonosis caused by protozoa of the family Piroplasmorida, which includes Babesia and Theileria species. In the United States, the infection is endemic in the Northeast and upper Midwest, although cases have recently been described in Northern California and Washington State. We report a case of babesiosis in a patient infected with HIV who presented with a prolonged fever of unknown origin; the patient had not undergone splenectomy. Parasitemia persisted despite initial clinical improvement after treatment with quinine and clindamycin. Babesiosis was controlled with a maintenance regimen consisting of clindamycin, doxycycline, and high-dose azithromycin, but the infection was not eradicated. Babesiosis should be considered in the differential diagnosis of HIV-infected patients with fevers and/or anemia in areas where the infection is endemic. HIV-infected patients who are severely immunosuppressed, even those without a history of splenectomy, may present with severe manifestations of babesiosis and develop a chronic infection, which may require therapy to prevent relapse of disease.