Malaria is a major health problem in the tropics, with 300-500 million new clinical cases annually, most of them cases of uncomplicated malaria. An estimated 1.1-2.7 million deaths occur annually as a result of severe falciparum malaria. Uncomplicated malaria can progress to severe malaria, become chronic, or resolve, depending on host immunity and prompt access to appropriate treatment.We conducted a systematic review and aimed to answer the following clinical questions: Are artemisinin combination treatments more effective than non-artemisinin combination treatments in people living in endemic areas (excluding South East Asia)? Which artemisinin combination treatment is most effective in people living in endemic areas? We searched: Medline, Embase, The Cochrane Library and other important databases up to November 2006 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).We found 18 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.In this systematic review we present information relating to the effectiveness and safety of the following interventions: amodiaquine plus sulfadoxine-pyrimethamine, artemether-lumefantrine, artesunate plus mefloquine, artesunate plus amodiaquine, and artesunate plus sulfadoxine.