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As part of an effort to assess antimalarial drug resistance in Peru, we carried out 14-day in vivo efficacy trials of chloroquine (CQ; 25 mg/kg) and sulfadoxine-pyrimethamine (SP; 25 mg/kg of the sulfadoxine component) for the treatment of uncomplicated Plasmodium falciparum infections at three sites on the northern coast of Peru. Mefloquine (MQ; 15 mg/kg) also was evaluated at one site. The results from all three sites were similar. Of the 53 patients treated with CQ, 58.5% had RII/RIII responses. No RIII failures were observed among the 112 patients who received SP, but 4.5% and 1.8%, respectively, had RII and RI responses. All 33 patients treated with MQ showed a sensitive response. Early treatment failures were observed in 27.1% of the CQ patients but in no patients receiving SP or MQ. Late treatment failures were seen in 59.3% of the CQ patients and 6.4% of the SP patients but in none of those treated with MQ. Based on these findings and because of concern about the potential for development of resistance if SP were used alone, the National Malaria Control Program is planning a change in malaria treatment policy to SP-artesunate combination therapy for this region of the country.