The purpose of this study was to update efficacy data of Artesunate-Amodiaquine (AS+AQ) and Artemether-Lumefantrine (AL) used as first-line malaria treatment in Côte d'Ivoire since 2005. This was an open-label, randomized trial conducted in patients older than 6 months with uncomplicated P. falciparum malaria at six sentinel sites. The WHO 2009 protocol on surveillance of anti-malaria drug efficacy was used with primary outcomes as ACPR corrected by PCR at day 42. Secondary endpoints were parasite and fever clearance times and safety. From January to July 2016, 712 patients were included in the trial. 353 and 359 patients were randomly assigned respectively to the AS+AQ and AL arm. Day 42 PCR-adjusted ACPR in the per-protocol analysis was 99.4% and 98.8% in AS+AQ and AL arm respectively. Delayed parasite clearance was observed in six patients at Abidjan and Yamousssoukro sites. Both ACTs were well tolerated. Both ACTs remain efficacious for uncomplicated P. falciparum malaria treatment in Côte d'Ivoire. But regarding delayed parasite clearance observed in this study, a close monitoring and supervision for ACT resistance are essential for future malaria treatment and control strategies in Côte d'Ivoire.