Malaria remains a major public health problem in Côte d’Ivoire. The aim of this study is to compare the efficacy and tolerability of artesunate-amodiaquine (ASAQ) versus artemether-lumefantrine (AL) for the treatment of uncomplicated malaria, at two malaria surveillance sites in Côte d’Ivoire. The World Health Organization 2003 protocol was used for this multicenter open randomized clinical trial with a 42-day follow-up. We recruited 240 patients (120 per arm), of whom 114 (ASAQ group) and 112 (AL group) were fully followed-up. According to intention-to-treat statistical analysis, PCR-corrected cure rates for ASAQ and AL treatments were 95.8% and 92.5% on day 28, and 95% and 92.5% on day 42, respectively. Based on per-protocol statistical analysis, ASAQ and AL treatment rates reached 100% and 99.1%, respectively, on day 28 and remained the same on day 42. Overall, both drugs were well-tolerated at the clinical and biological level. This study shows that ASAQ and AL are still effective and well-tolerated. Accordingly, they can continue being used to treat uncomplicated malaria in Côte d’Ivoire. However, monitoring of their efficacy should remain a priority for health authorities.