Effective and affordable treatment of malaria is critical in the face of resistance of Plasmodium falciparum to chloroquine (CQ) and sulfadoxine-pyrimethamine (SP). We conducted a randomized controlled trial comparing the efficacy of chlorproguanil-dapsone (CD) with a combination SP plus CQ in children in Nigeria less than five years of age with malaria. Of 264 children enrolled, 122 (89.7%) and 118 (92.2%) completed the study in the SP + CQ and CD groups, respectively. By day 3, 96 (78.7%) and 94 (79.7%) had cleared their parasitemia (P = 0.79), and 107 (87.7%) and 109 (92.4%) were symptom free (P = 0.32) in the SP + CQ and CD groups, respectively. Adequate clinical and parasitologic response at day 14 occurred in 111 (94.1%; 95% confidence interval [CI] = 91.6-95.7%) in the CD group and 113 (92.6%; 95% CI = 89.9-94.3%) in the SP + CQ group (P = 0.85). SP + CQ and CD had similar antimalarial efficacy and still provide affordable treatment of uncomplicated malaria in northcentral Nigeria.