In 2001, Peru changed its treatment policy for uncomplicated Plasmodium falciparum malaria on the northern Pacific Coast to sulfadoxine-pyrimethamine with atresunate (SP-AS). Because Peru was the first country in the Americas to adopt this combination therapy, we established a surveillance system in the region to assess the frequency of new or worsening symptoms after starting therapy. Over a period of two years, 1,552, or approximately two-thirds of all patients with uncomplicated P. falciparum malaria who had received SP-AS on the northern coast were followed up. Of these, 8.8% reported at least one adverse effect, with the most common being vomiting, nausea, headache, abdominal pain, dizziness, and fever; no severe adverse effects related to SP-AS therapy were identified. Treatment of uncomplicated malaria with SP-AS was associated with a low frequency of mild adverse effects in Peru, and therefore should be considered as a first-line therapy in areas of the Americas where SP efficacy is still high.