This double-blind study is based on the treatment of 75 adult male patients suffering from Plasmodium falciparum malaria in Medellín, Colombia, a city in which there is no malaria transmission. The patients, who came from regions with high resistance to antimalarials, were divided into three groups receiving single-dose treatment as follows: a combination of 280 mg mefloquine, 800 mg sulfadoxine and 40 mg pyrimethamine; a combination of 420 mg mefloquine, 1200 mg sulfadoxine and 60 mg pyrimethamine; and a combination of 1500 mg sulfadoxine and 75 mg pyrimethamine. After treatment, follow-up examination was performed daily for I week and then weekly for another 3 weeks. The cure rate in the mefloquine groups (within the study period of 28 days) was 100%, and in the third group 75%. Normal blood levels of the administered drugs were found in 6 patients of the third group who were not cured; they were subsequently cured with a single dose of 1000 mg of mefloquine. Drug tolerance was good and no toxic effects were demonstrated in blood and urine examinations. While the doses in the drug combinations (containing mefloquine) gave very good results, we would recommend a slightly higher dose combination of mefloquine with sulfadoxine-pyrimethamine for the treatment of falciparum malaria in areas with a high prevalence of chloroquine resistance.