Malaria still remains a major public health problem in Ethiopia. Early diagnosis and promptrntreatment of malaria cases is a primary malaria control strategy in the country. However, thisrncontrol strategy is severely challenged by the evolution and rapid spread of resistant P.rnfalciparum strains. Artemether-lumefantine (Art-L) is the first-line antimalarial drug againstrnuncomplicated P. falciparum malaria in the country since 2004. Regular monitoring of first- andrnsecond-line antimalarial drugs is recommended by the World Health Organization (WHO) tornhelp early detection of drug resistance and search for more effective options. However, there isrnno data regarding the efficacy status of AL in Setit Humera, northwest Ethiopia. This study was,rntherefore, conducted to fill in this gap. One arm prospective study of a 28-day follow-up wasrnconducted from October 2014 to January 2015 according to the revised WHO 2009 efficacyrnstudy protocol. Study outcomes were classified into primary and secondary. The primary studyrnoutcome was the day 28 adequate clinical and parasitological response. The secondary studyrnoutcomes were clinical and parasitological evaluations (parasite, fever and gametocyte clearancernrate, incidence of drug adverse events) and the relative increment in hemoglobin level fromrnbaseline to day (D) 14 and D28. A total of 92 patients were enrolled and 80 had completed thern28-day follow-up period. The overall cure rate was 98.8% with 95% confidence interval (0.915-rn0.998) without polymerase chain reaction correction. The parasite clearance rate was high withrnfast resolution of clinical symptoms; 100% of the study participants cleared parasitaemia andrnfever on D3. Gametocyte carriage was reduced from 7% on D0 to 1% on D3 and completernclearance was achieved on D21. Mean hemoglobin concentration has significantly increased onrnD28 compared to that of D14. There was no serious adverse event. Overall, AL was efficaciousrnand safe in the study population for treatment of uncomplicated falciparum malaria.