OBJECTIVE: To compare the efficacy of sulfadoxine-pyremethamine (SP)+chloroquine (CQ) combination treatment against falciparum malaria with SP treatment alone. METHOD: In-vivo study of 254 patients with uncomplicated Plasmodium falciparum malaria in rural eastern Sudan, where the population is semi-immune. RESULTS: Sulfadoxine-pyremethamine treatment alone cured 68.3% (41/60) and SP+CQ cured 63.4% (123/194). Early and late treatment failures occurred in both treatment groups. Host age (as a marker for immunity) and parasite gametocytogenesis (as a marker for transmissibility) were significantly associated with SP resistance. Patients who were cured were significantly older (median age 21 years) than patients whose treatment failed (median age 12 years). Gametocyte production was significantly higher in patients with treatment failure (0.72 vs 0.45) and associated with younger age. Gametocyte counts were comparable between both groups until day 7 of follow up; thereafter, they were significantly higher in patients with treatment failure. However, the longevity of gametocytes was comparable in both treatment groups. CONCLUSION: Chloroquine did not improve the parasite response to SP. Age was strongly associated with clearance of SP-resistant parasites. The fast rise of SP resistance may partially be due to selection of SP resistant parasites and expansion of the resistant population through the gametocytogenic effect of SP.