Artemisinin-based combination therapy (ACT) is the first-line antimalarial regimen in Indonesia. Susceptibility of Plasmodium falciparum to artemisinin is falling in the Greater Mekong subregion, but it is not known whether the efficacy of current combinations is also threatened in nearby Sumatera. We evaluated the genetic loci pfcrt, pfmdr1, and pfk13, considered to be under selection by artemisinin combination therapy, among 404 P. falciparum infections identified by PCR detection in a cross-sectional survey of 3,731 residents of three regencies. The pfcrt haplotype SVMNT (codons 72 to 76) was the most prevalent and displayed significant linkage disequilibrium with the pfmdr1 haplotype YY (codons 86 and 184) (odds ratio [OR] 26.7; 95% confidence interval [CI], 5.96 to 239.4; P < 0.001). This contrasts with Mekong countries, where the CVIET haplotype of pfcrt predominates. Among 231 evaluable isolates, only 9 (3.9%) showed any evidence of nonsynonymous gene variants in the propeller domain of pfk13 The Thr474Ala variant was seen in six individuals, and Cys580Tyr was identified with low confidence in only a single isolate from an asymptomatic individual. Among a subset of 117 symptomatic P. falciparum-infected individuals randomized to receive either dihydroartemisinin-piperaquine or artemether-lumefantrine, the treatment outcome was not associated with pretreatment genotype. However, submicroscopic persistent parasites at day 28 or day 42 of follow-up were significantly more likely to harbor the pfmdr1 haplotype NF (codons 86 and 184) than were pretreatment isolates (P < 0.001 for both treatment groups). Current ACT regimens appear to be effective in Sumatera, but evidence of persistent submicroscopic infection in some patients suggests further detailed studies of drug susceptibility should be undertaken.