Summary In 1993, Malawi replaced chloroquine (CQ) with sulphadoxine-pyrimethamine (SP) as its first-line treatment for uncomplicated malaria in children < 5 years of age. To assess the efficacy of SP after 5 years of widespread use, we undertook this study at 7 sites in 6 districts of Malawi. Febrile children < 5 years attending the outpatient clinics of selected hospitals whose parents consented were enrolled in the study if they had an axillary temperature of ≥ 37.5 °C and pure Plasmodium falciparum parasitaemia of ≥ 2000 asexual parasites/mm3. They were then followed for 14 days or until clinical failure. Parasitological resistance rates (RII and RIII) ranged from 7% to 19%. Resistance was higher in the north than in the central and southern regions, although this difference was not statistically significant. Resistance rates were a mean 19% during the rainy season vs. 12% in the dry season (P > 0.05). 80% of parasitological resistance was at the RII level. Of all children who failed parasitologically (90/641), 84 (93%) had no fever on day 7 and their mothers did not report them as being ill; only 6 of 641 (0.9%) patients met the WHO criteria for clinical treatment failure. Regardless of study site, 75% of mothers reported their children as having improved by day 3; 90% reported improvement by day 7, and all reported improvement by day 14. None of the children experienced any serious adverse reactions and none died. We found that after more than 5 years of widespread use of SP in Malawi, its efficacy remains acceptable for treatment of uncomplicated malaria, and it should therefore be retained as first-line treatment.