Objective Our objective was to characterize the pharmacokinetic properties of sulfadoxine‐pyrimethamine in African adults and children with acute falciparum malaria. Despite decades of widespread use, there are few data to inform dose recommendations. Methods In a prospective multicenter pharmacokinetic study in 307 patients with acute falciparum malaria, capillary blood concentrations of sulfadoxine and pyrimethamine were determined at 9 visits over a period of 42 days by mass spectrometry. Results After adjustment for dose, the area under the concentration‐time curves (AUCs) of sulfadoxine and pyrimethamine in children aged 2 to 5 years were half of those in adults (median AUC, 410 μg/mL · d [interquartile range (IQR), 126‐705 μg/mL · d] versus 816 μg/mL · d [IQR, 536‐1150 μg/mL · d] [P = .0001] for sulfadoxine and 620 ng/mL · d [IQR, 229‐1399 ng/mL · d] versus 1518 ng/mL · d [IQR, 1117‐2013 ng/mL · d] for pyrimethamine). The effect of age on the AUC of sulfadoxine and pyrimethamine reflected higher clearance rates and larger apparent volumes of distribution in children aged 2 to 5 years when compared with adults (median clearance, 64.5 mL · kg−1 · d−1 [IQR, 46.2‐132.6 mL · kg−1 · d−1] versus 32.7 mL · kg−1 · d−1 [IQR, 22.3‐52.2 mL · kg−1 · d−1] for sulfadoxine [P = .0001] and 1.77 L · kg−1 · d−1 [IQR, 1.0‐3.0 L · kg−1 · d−1] versus 0.85 L · kg−1 · d−1 [IQR, 0.62‐1.21 L · kg−1 · d−1] for pyrimethamine [P = .0001]; median volume of distribution, 413 mL/kg [IQR, 299‐711 mL/kg] versus 372 mL/kg [IQR, 267‐488 mL/kg] for sulfadoxine [P = .0021] and 6.28 L/kg [IQR, 3.83‐11.24 L/kg] versus 3.83 L/kg [IQR, 2.73‐5.11 L/kg] for pyrimethamine [P = .0001]). Day 7 concentrations of both sulfadoxine and pyrimethamine provided good surrogate measures (R2 ≥ 0.72) of their respective AUCs. Conclusions Pharmacokinetic factors may contribute to the increased risk of sulfadoxine‐pyrimethamine antimalarial treatment failure in young children. The current dose recommendations need revision. We predict that children aged 2 to 5 years should be treated with 1 g sulfadoxine/50 mg pyrimethamine to achieve drug concentrations equivalent to those in adults. Clinical Pharmacology & Therapeutics (2006) 80, 582–596; doi: 10.1016/j.clpt.2006.08.016