Sulfadoxine-pyrimethamine (SP) is the current first-line treatment for uncomplicated malaria in Malawi. The malaria parasite P. falciparum has developed resistance to this drug so that the drug is much less effective than in previous years. This study was developed and conducted in collaboration with the National Malaria Control Programme of Malawi to assess the efficacy of four antimalarial drug combinations to provide evidence to assist the Malawian Ministry of Health in identifying and implementing as policy the next first-line antimalarial for uncomplicated malaria in Malawi. In an open, randomized trial in children under five years of age, four drug combinations, all of which are licensed in Malawi, are being assessed: amodiaquine plus sulfadoxine-pyrimethamine (AQ-SP), amodiaquine plus artesunate (AQ-Art), chlorproguanil-dapsone plus artesunate (CD-Art) and lumefantrine-artemether (LA). SP is also included as a fifth arm of the study for current data on its efficacy. Data on side effects of the drugs will also be collected. The results of this study will provide some of the information necessary to guide the Malawi National Malaria Control Program in selecting its next first antimalarial treatment for uncomplicated malaria. The study adheres to the World Health Organization's 2003 standardized protocol for assessing antimalarial drug efficacy.