During May 4, 2007-February 29, 2008, the United States resettled 6,159 refugees from Tanzania. Refugees received pre-departure antimalarial treatment with sulfadoxine-pyrimethamine (SP), partially supervised (three/six doses) artemether-lumefantrine (AL), or fully supervised AL. Thirty-nine malaria cases were detected. Disease incidence was 15.5/1,000 in the SP group and 3.2/1,000 in the partially supervised AL group (relative change = -79%, 95% confidence interval = -56% to -90%). Incidence was 1.3/1,000 refugees in the fully supervised AL group (relative change = -92% compared with SP group; 95% confidence interval = -66% to -98%). Among 39 cases, 28 (72%) were in refugees &λτ; 15 years of age. Time between arrival and symptom onset (median = 14 days, range = 3-46 days) did not differ by group. Thirty-two (82%) persons were hospitalized, 4 (10%) had severe manifestations, and 9 (27%) had parasitemias &γτ; 5% (range = &λτ; 0.1-18%). Pre-departure presumptive treatment with an effective drug is associated with decreased disease among refugees.