Babesiosis is a tick-borne, malaria-like illness known to be enzootic in southern New England. A course of clindamycin and quinine is the standard treatment, but this regimen frequently causes adverse reactions and occasionally fails. A promising alternative treatment is atovaquone plus azithromycin. We conducted a prospective, nonblinded, randomized trial of the two regimens in 58 subjects with non-life-threatening babesiosis on Nantucket, on Block Island, and in southern Connecticut. The subjects were assigned to receive either atovaquone (750 mg every 12 hours) and azithromycin (500 mg on day 1 and 250 mg per day thereafter) for seven days (40 subjects) or clindamycin (600 mg every 8 hours) and quinine (650 mg every 8 hours) for seven days (18 subjects). Adverse effects were reported by 15 percent of the subjects who received atovaquone and azithromycin, as compared with 72 percent of those who received clindamycin and quinine (P<0.001). The most common adverse effects with atovaquone and azithromycin were diarrhea and rash (each in 8 percent of the subjects); with clindamycin and quinine the most common adverse effects were tinnitus (39 percent), diarrhea (33 percent), and decreased hearing (28 percent). Symptoms had resolved three months after the start of therapy in 65 percent of those who received atovaquone and azithromycin and 73 percent of those who received clindamycin and quinine (P=0.66), and after six months no patient in either group had symptoms. Three months after the completion of the assigned regimen, no parasites could be seen on microscopy, and no Babesia microti DNA was detected in the blood of any subject. For the treatment of babesiosis, a regimen of atovaquone and azithromycin is as effective as a regimen of clindamycin and quinine and is associated with fewer adverse reactions.