. Malaria has rebounded significantly in 2018 in the Comoros. It posed an urgent need to conduct clinical trials to investigate the effectiveness of artemisinin and its derivatives there.. From June 2019 and January 2020, an open-label, non-randomized controlled trial of artemisinin-piperaquine (AP) and artemether-lumefantrine (AL) were conducted in Grande Comore Island. 238 uncomplicated falciparum malaria cases were enrolled and divided 1:1 into two treatments. The primary endpoint was the 42-day adequate clinical and parasitological responses (ACPR). Parasitemia and fever clearance at day 3, gametocyte, and tolerability were secondary endpoints.. The 42-day ACPR before and after PCR-corrected were 91.43% [95% confidence interval (CI): 83.93%-95.76%] and 98.06% [95%CI: 92.48%-99.66%] for AP treatment, respectively, and 96.00% [95%CI: 88.17%-98.14%] and 98.97% [95%CI: 93.58%-99.95%] for AL treatment, respectively. Complete clearance of the parasitemia as well as of fever for both groups was detected on day 3. Gametocytes disappeared on day 21 in the AP group and on day 2 in AL group, respectively. Specifically, the adverse reactions were mild in both groups.We discovered that AP and AL maintained their high efficacy and tolerance in the Comoros. Nonetheless, asymptomatic malaria infections bring new challenges to malaria control.Copyright © 2022. Published by Elsevier Ltd.