OBJECTIVE To measure the efficacy of sulfadoxine-pyrimethamine treatment of falciparum malaria in Malawi from 1998 to 2002, after a change from chloroquine to sulfadoxine-pyrimethamine as first line treatment in that country in 1993. DESIGN Prospective open label drug efficacy study. SETTING Health centre in large peri-urban township adjacent to Blantyre, Malawi. PARTICIPANTS People presenting to a health centre with uncomplicated Plasmodium falciparum malaria. MAIN OUTCOME MEASURES Therapeutic efficacy and parasitological resistance to standard sulfadoxine-pyrimethamine treatment at 14 days and 28 days of follow up. RESULTS Therapeutic efficacy remained stable, with adequate clinical response rates of 80% or higher throughout the five years of the study. Analysis of follow up to 28 days showed modest but significant trends towards diminishing clinical and parasitological efficacy over time within the study period. CONCLUSION Contrary to expectations, sulfadoxine-pyrimethamine has retained good efficacy after 10 years as the first line antimalarial drug in Malawi. African countries with very low chloroquine efficacy, high sulfadoxine-pyrimethamine efficacy, and no other immediately available alternatives may benefit from interim use of sulfadoxine-pyrimethamine while awaiting implementation of combination antimalarial treatments.