High levels of Plasmodium falciparum resistance to both chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) have been documented throughout the Amazon Basin of South America. Because of reports about the persistent efficacy of both of these drugs in the northwestern Peruvian Amazon region, we carried out an evaluation of the therapeutic efficacy of chloroquine (25 mg/kg) and SP (25 mg/kg of the sulfadoxine component) for the treatment of uncomplicated P. falciparum infections at two sites: Ullpayacu and Pampa Hermoza/Alianza. A total of 111 patients were enrolled. Only 5 (14.3%) of the 35 patients who received CQ had an adequate clinical and parasitologic response (ACPR). Six subjects (17%) had early treatment failure, 1 (2.9%) had late clinical failure, and 23 (65.7%) had late parasitologic failure (LPF). Of the subjects treated with SP, 92.3% had ACPR and 7.7% had LPF. Based on these findings, it is clear that there are at least limited areas within the Peruvian Amazon region where P. falciparum strains continue to be sensitive to SP. Copyright © 2007 by The American Society of Tropical Medicine and Hygiene.