To assess the therapeutic efficacy of sulfadoxinepyrimethamine (SP) after 5 years of use as first-line treatment of uncomplicated Plasmodium falciparum malaria, and thus guide the selection of artemisinin-based combination therapy in Mpumalanga, South Africa.An open-label, in vivo therapeutic efficacy study of patients with uncomplicated P. falciparum malaria treated with a single oral dose of SP, with response to treatment monitored clinically and parasitologically on days 1, 2, 3, 7, 14, 21, 28 and 42.Mangweni and Naas public health care clinics, Tonga district in rural Mpumalanga. SUBJECTS, OUTCOME MEASURES AND RESULTS: Of 152 patients recruited sequentially, 149 (98%) were successfully followed up for 42 days. One hundred and thirty-four patients (90%) demonstrated adequate clinical and parasitological response. Of the 15 patients (10%) who failed treatment, 2 (1.3%) had an early treatment failure, and polymerase chain reaction confirmed recrudescent infection in all 13 patients (8.7%) who had late parasitological (N = 11) or clinical (N = 2) failure. Gametocyte carriage was prevalent following SP treatment (84/152) and this has increased significantly since implementation in 1998 (relative risk 2.77 (confidence interval 1.65 - 4.66); p = 0.00004).Asexual P. falciparum parasites in Mpumalanga remain sensitive to SP, with no significant difference between the baseline cure rate (94.5%) at introduction in 1998, and the present 90% cure rate (p = 0.14). However, since gametocyte carriage has increased significantly we recommend that SP be combined with artesunate in Mpumalanga to reduce gametocyte carriage and thus decrease malaria transmission and potentially delay antimalarial resistance.