Background: Artemisinin combination therapies have been wildly used in the treatment of uncomplicated falciparum malaria in most endemic countries. This strategy has been implemented in Côte d'Ivoire since 2005 with Artesunate + Amodiaquine (AS + AQ) and Artemether + lumefantrine (AL). The goal of this study was to assess efficacy and safety of these two drugs in two sentinel's sites, Man and Abidjan in Côte d'Ivoire.Methods: An open label, randomized, clinical trial was conducted in Man in the west and Abidjan in the south of Côte d'Ivoire. Patients older than 6 months with uncomplicated falciparum malaria after consent were randomized in AS+AQ and AL group and were followed up for 42 days.The first endpoint was Adequate Clinical and Parasitological Response adjusted by PCR at day 42. The second endpoints were fever and parasite clearance time, crude cure rate at day 42 and safety of the two ACTs.Results: A total of 241 patients were randomized in AS+AQ (120) and AL (121) group. The crude cure rate at day 42 in PP analysis was 95.8% and 87.9% in AS+AQ and AL respectively. After correction by PCR ACPR at day 42 was 99.2% in AS+AQ group and 97.4% in AL group. The two ACTs were well tolerated. Conclusion:AS+AQ and AL remains efficacious in the uncomplicated malaria treatment in the two areas but continue monitoring is needed particularly for AL.