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Introduction. Multidrug resistance of Plasmodium falciparum is spreading throughout Africa. This has posed major challenges to malaria control in sub-Saharan Africa. Objective. The aim of the study was to evaluate the efficacy of artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in North Ethiopia. Methods. This prospective study was undertaken during August-November 2009 on 71 malaria patients that fulfilled the inclusion criteria set by the WHO. Patients were followed up for 28 days. Thick and thin blood films were prepared by Giemsa stain for microscopy to determine parasite density. A standard six-dose regimen of artemether-lumefantrine was administered over three days and was followed up with clinical and parasitological evaluations over 28 days. Results. The cure rate (ACPR) was found to be high (97.2%) in this study. The parasite and fever clearance time was also rapid. Artemether-lumefantrine for the treatment of acute uncomplicated Plasmodium falciparum malaria in the study area showed 97.2% cure rate and only 2.8% failure rate. Conclusion. The result showed that the drug could continue as first line for the treatment of uncomplicated Plasmodium falciparum malaria in the study area. The efficacy of artemether-lumefantrine needs to be carefully monitored periodically in sentinel sites representing different areas of the country. [ABSTRACT FROM AUTHOR]