The WHO recommends that children living in areas of highly seasonal malaria transmission in the Sahel subregion should receive seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine plus amodiaquine (SPAQ). We evaluated the use of dihydroartemisinin-piperaquine (DHAPQ) as an alternative drug that could be used if SPAQ starts to lose efficacy. A total of 1,499 children 3 to 59 months old were randomized to receive SMC with SPAQ or DHAPQ over 3 months. The primary outcome measure was the risk of clinical malaria (fever or a history of fever with a parasite density of at least 3,000/μl). A cohort of 250 children outside the trial was followed up as a control group. Molecular markers of drug resistance were assessed. The risk of a malaria attack was 0.19 in the DHAPQ group and 0.15 in the SPAQ group, an odds ratio of 1.33 (95% confidence interval [CI], 1.02 to 1.72). Efficacy of SMC compared to the control group was 77% (67% to 84%) for DHAPQ and 83% (74% to 89%) for SPAQ. pfdhfr and pfdhps mutations associated with antifolate resistance were more prevalent in parasites from children who received SPAQ than in children who received DHAPQ. Both regimens were highly efficacious and well tolerated. DHAPQ is a potential alternative drug for SMC. (This trial is registered at ClinicalTrials.gov under registration no. NCT00941785.).