This randomized, open-label study compared a three-day, six-dose regimen of artemether-lumefantrine with a five-day, 19-dose regimen of quinine-doxycycline for the treatment of Plasmodium falciparum malaria in the western Amazon region of Brazil. All patients remained hospitalized during their treatment and the study assessments were scheduled daily from the start of treatment (day 0) through day 6. By day 3, the percentage of infected patients was 0% in the artemether-lumefantrine group and 48.8% in the quinine-doxycycline group. Median parasite clearance time was significantly shorter in the artemether-lumefantrine group (two days) compared with the quinine-doxycycline group (three days) (P < 0.0001). Two patients in the quinine-doxycycline group left the study early because of treatment ineffectiveness or adverse event. Adverse events were reported by 91.5% of the study participants, most of which were mild in severity and/or not considered related to study treatment. Artemether-lumefantrine was shown to be an efficacious, safe, and convenient treatment for P. falciparum malaria in a highly drug-resistant region of South America.