ABSTRACT The pharmacogenetics of antimalarial agents are poorly known, although the application of pharmacogenetics might be critical in optimizing treatment. This population pharmacokinetic-pharmacogenetic study aimed at assessing the effects of single nucleotide polymorphisms (SNPs) in cytochrome P450 isoenzyme genes ( CYP , namely, CYP2A6 , CYP2B6 , CYP2C8 , CYP2C9 , CYP2C19 , CYP2D6 , CYP3A4 , and CYP3A5 ) and the N -acetyltransferase 2 gene ( NAT2 ) on the pharmacokinetics of artemisinin-based combination therapies in 150 Tanzanian patients treated with artemether-lumefantrine, 64 Cambodian patients treated with artesunate-mefloquine, and 61 Cambodian patients treated with dihydroartemisinin-piperaquine. The frequency of SNPs varied with the enzyme and the population. Higher frequencies of mutant alleles were found in Cambodians than Tanzanians for CYP2C9 * 3 , CYP2D6 * 10 (100C→T), CYP3A5 * 3 , NAT2 * 6 , and NAT2 * 7 . In contrast, higher frequencies of mutant alleles were found in Tanzanians for CYP2D6 * 17 (1023C→T and 2850C→T), CYP3A4 * 1B , NAT2 * 5 , and NAT2 * 14 . For 8 SNPs, no significant differences in frequencies were observed. In the genetic-based population pharmacokinetic analyses, none of the SNPs improved model fit. This suggests that pharmacogenetic data need not be included in appropriate first-line treatments with the current artemisinin derivatives and quinolines for uncomplicated malaria in specific populations. However, it cannot be ruled out that our results represent isolated findings, and therefore more studies in different populations, ideally with the same artemisinin-based combination therapies, are needed to evaluate the influence of pharmacogenetic factors on the clearance of antimalarials.