• Both artemisinin-piperaquine and artemether-lumefantrine maintained high efficacy during the treatment of falciparum malaria in Grande Comore island. • Artemisinin-piperaquine in combination with anti-gametocyte treatment is recommended for rapidly increasing the killing effect of the malaria gametocyte in areas with a high rate of carrying. • Asymptomatic parasitaemia infections bring new challenges for malaria control in Comoros. Malaria significantly rebounded in 2018 in the Comoros; this created an urgent need to conduct clinical trials to investigate the effectiveness of artemisinin and its derivatives. An open-label, non-randomised controlled trial of artemisinin-piperaquine (AP) and artemether-lumefantrine (AL) was conducted in Grande Comore island from June 2019 to January 2020. A total of 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). Secondary endpoints were parasitaemia and fever clearance at day 3, gametocytes and tolerability. The 42-day ACPR before and after PCR correction were 91.43% (95% 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 parasitaemia and 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. Specifically, the adverse reactions were mild in both groups. It was found that AP and AL maintained their high efficacy and tolerance in the Comoros. Nonetheless, asymptomatic malaria infections bring new challenges to malaria control. [ABSTRACT FROM AUTHOR]