A three-arm, parallel, double-blind, randomised controlled trial conducted among asymptomatic children aged 3–5 years in Cameroon to assess parasite clearance and protection from Plasmodium falciparum infection following antimalarial chemoprevention. Eligible children were randomly assigned to one of three directly-observed treatment groups: sulfadoxine–pyrimethamine (SP), sulfadoxine–pyrimethamine plus amodiaquine (SP–AQ), or no chemoprevention (artesunate monotherapy). Participants were followed longitudinally with regular clinical assessments and provided blood for thick smear slides, and dried blood spots for quantitative polymerase chain reaction (qPCR) and genotype analyses. The aim of the study was to measure the chemopreventive efficacy of SP, and SP plus AQ, and quantify the effect on both parasite clearance and protection from infection against parasite genotypes associated with drug resistance. Study drugs and outcome assessments were masked to participants and study staff. See the associated publication for full details on eligibility criteria, intervention regimens, follow-up procedures, and outcome definitions.