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Abstract Background Artemether/Lumefantrine (Coartem®) has been used as a first-line treatment for uncomplicated Plasmodium falciparum infection since 2004 in Ethiopia. In the present study the therapeutic efficacy of artemether/lumefantrine for the treatment of uncomplicated P. falciparum infection at Kersa, Jima zone, South-west Ethiopia, has been assessed. Methods A 28 day therapeutic efficacy study was conducted between November 2007 and January 2008, in accordance with the 2003 WHO guidelines. Outcomes were classified as early treatment failure (ETF), late clinical failure (LCF), late parasitological failure (LPF) and adequate clinical and parasitological response (ACPR). Results 90 patients were enrolled and completed the 28 day follow-up period after treatment with artemether/lumefantrine. Cure rate was very high, 96.3%, with 95% CI of 0.897-0.992 (PCR uncorrected). Age-stratified data showed adequate clinical and parasitological response (ACPR) to be 100% for children under 5 and 97.4% and 87.3% for children aged 5-14, and adults, respectively. There was no early treatment failure (ETF) in all age groups. Fever was significantly cleared on day 3 (P < 0.05) and 98% of parasites where cleared on day 1 and almost all parasites were cleared on day 3. 72.5% of gametocytes were cleared on day 1, the remaining 27.5% of gametocytes were maintained up to day 3 and total clearance was observed on day 7. Hemoglobin concentration showed a slight increase with parasitic clearance (P > 0.05). No major side effect was observed in the study except the occurrence of mouth ulcers in 7% of the patients. Conclusions The current study proved the excellent therapeutic efficacy of artemether/lumefantrine in the study area and the value of using it. However, the proper dispensing and absorption of the drug need to be emphasized in order to utilize the drug for a longer period of time. This study recommends further study on the toxicity of the drug with particular emphasis on the development of oral ulcers in children.