The 4-aminoquinolines, chloroquine or amodiaquine, have long been the drugs of choice for treating uncomplicated, falciparum malaria in Africa, although resistance to them is now common. Sulfadoxine-pyrimethamine (SP) is the usual alternative when 4-aminoquinoline treatment fails. A combination-treatment regimen could combine the rapid symptom relief offered by the 4-aminoquinolines with the prolonged parasiticidal activity of SP, and also slow down development of resistance to the individual drugs. A systematic review of randomized trials was conducted so that the evidence of effectiveness and safety of such combination treatment could be summarized and compared with the results of treatment with either drug given alone. The results of trials were sought by searching through electronic databases and by contact with researchers in the field. Five studies were identified. Although there are few data, there is evidence that control of clinical symptoms is better when a 4-aminoquinoline is used with SP than when SP is used alone, and the cure rate also tends to be higher with the combination regimen. No evidence of serious side-effects was found. Larger scale trials are needed if this combination is to be adopted more widely.