We tested tafenoquine (WR 238605), a new long-acting 8-aminoquinoline, for its ability to prevent malaria in an area that is holoendemic for Plasmodium falciparum. In a double-blinded, placebo-controlled, randomized clinical trial in western Kenya, adult volunteers received a treatment course of 250 mg halofantrine per day for 3 days, to effect clearance of preexisting parasites. The volunteers were then assigned to 1 of 4 drug regimens: placebo throughout; 3 days of 400 mg (base) of tafenoquine per day, followed by placebo weekly; 3 days of 200 mg of tafenoquine per day, followed by 200 mg per week; and 3 days of 400 mg of tafenoquine per day, followed by 400 mg per week. Prophylaxis was continued for up to 13 weeks. Of the evaluable subjects (223 of 249 randomized subjects), volunteers who received 400 mg tafenoquine for only 3 days had a protective efficacy of 68% (95% confidence interval [CI], 53%-79%), as compared with placebo recipients; those who received 200 mg per day for 3 days followed by 200 mg per week had a protective efficacy of 86% (95% CI, 73%-93%); and those who received 400 mg for 3 days followed by 400 mg per week had a protective efficacy of 89% (95% CI, 77%-95%). A similar number of volunteers in the 4 treatment groups reported adverse events. Prophylactic regimens of 200 mg or 400 mg of tafenoquine, taken weekly for < or =13 weeks, are highly efficacious in preventing falciparum malaria and are well tolerated.