This study is a cost-benefits analysis of the recommendations of the Centers for Disease Control and Prevention for presumptive anti-malarial treatment among departing West African refugees. We conducted a retrospective chart review of symptomatic, blood smear-positive cases of malaria seen in Minneapolis, Minnesota, from 1996 through 2005. Billing charges of U.S. care were compared with estimates of implementation costs for overseas treatment. Fifty-eight symptomatic malaria infections occurred among West African refugees. After overseas pre-departure presumptive treatment, symptomatic malaria in arriving refugees decreased from 8.2% to 0%. The pre-departure number needed to treat to prevent one case of symptomatic malaria is 13.9 (95% confidence interval = 9.8-24). The average U.S. billing charge for each malaria case is $1,730. Overseas implementation costs for presumptive treatment are estimated to be between $141 and $346 to prevent one U.S. malaria case. Overseas presumptive pre-departure anti-malarial therapy prevents clinical malaria in refugees and results in cost-benefits when the malaria prevalence is > 1%. Overseas presumptive therapy has greater cost-benefits than U.S. based screening and treatment strategies.