Background: Artemether/lumefantrine (Coartem ®) has been used as a treatment for uncomplicated Plasmodium falciparum infection since 2004 in Benin. This open-label, non-randomized study evaluated efficacy of artemether-lumefantrine (AL) in treatment of uncomplicated falciparum malaria in children aged 6-59 months in two malaria transmission sites in northwest Benin.Methods: A 42-day therapeutic efficacy study was conducted between August and November 2014, in accordance with 2009 WHO guidelines. One-hundred and twenty-three children, aged 6 months to 5 years, with uncomplicated falciparum malaria were recruited into the study. The primary endpoint was parasitological cure on day 28 and day 42 while the secondary endpoints included: parasite and fever clearance, improvement in haemoglobin levels. Outcomes were classified as early treatment failure (ETF), late clinical failure, late parasitological failure, and adequate clinical and parasitological response (ACPR).Results: Before PCR correction, ACPR rates were 87 % (95 % CI 76.0-94.7) and 75.6 %, respectively (95 % CI 67.0-82.9) on day 28 and day 42. In each study site, ACPR rates were 78.3 % in Djougou and 73 % in Cobly on day 42. There was no ETF and after PCR correction ACPR was 100 % in study population. All treatment failures were shown to be due to new infections. Fever was significantly cleared in 24 h and approximately 90 % of parasites where cleared on day 1 and almost all parasites were cleared on day 2. Haemoglobin concentration showed a slight increase with parasitic clearance.Conclusion: AL remains an efficacious drug for the treatment of uncomplicated falciparum malaria in Benin, although higher rates of re-infection remain a concern. Surveillance needs to be continued to detect future changes in parasite sensitivity to artemisinin-based combination therapy.