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Children in areas of highly seasonal malaria transmission in the Sahel should receive SMC with sulfadoxine-pyrimethamine plus amodiaquine (SPAQ). These drugs retain their efficacy in the areas where SMC is recommended, but alternative regimens are needed if SMC is used in other areas or if these drugs start to lose efficacy. The aim of this study was to investigate the suitability of dihydroartemisin-piperaquine (DHAPQ) for SMC, using a non-inferiority trial design. 1500 children randomized to receive SPAQ or DHAPQ monthly from August to October, and a cohort of untreated children outside the trial, were followed-up for malaria. SPAQ was more efficacious than DHAPQ, but the difference was within the margin set for non-inferiority. Both regimens gave a very high level of protection lasting 4 weeks. Protection was related to dosage. Both regimens were well tolerated, incidence of mild adverse events decreased in successive months, consistent with toleration to study drugs. In malaria cases, the frequency of the CVIET haplotype of pfcrt, the 86Y polymorphism of pfmdr1, and pfdhfr59 and dhps437 mutations, was greater among children who received SPAQ than in untreated children. However the number of cases, and the prevalence of parasitaemia, was much lower in treated children, reducing the scope for SMC to select for resistance. The frequency of the CVIET haplotype of PfCRT, thought to be associated with resistance to PQ, was not increased in children treated with DHAPQ. There was an enormous burden of malaria in the untreated children. SMC with SPAQ should be introduced for children in Burkina Faso without delay. DHAPQ is a potential alternative regimen in areas where SPAQ cannot be used but there are some drawbacks associated with its use. There is a need to develop alternative long-acting drugs with simple regimens that can be used for chemoprevention of malaria.