Abstract Background Deployment of seasonal malaria chemoprevention (SMC) for young children using monthly sulphadoxine-pyrimethamine-amodiaquine (SPAQ) has recently been extended to Central and East Africa. Methods A pilot pharmacometric assessment was nested within a larger deployment of SMC in a high malaria transmission area in northern Mozambique. SPAQ was given to 460 healthy children in two large villages. Simultaneous filter-paper blood spot malaria quantitative PCRs, blood slide microscopy and antimalarial drug measurements were taken before, then 7 and 28 d after first SPAQ administration. Results After SPAQ, parasitaemia prevalence decreased from 68% to 41%. Among children followed successfully for 28 d, malaria parasitaemia prevalence declined from 71% to 44%. Preventive efficacy was 97% for Plasmodium ovale and 42% for Plasmodium falciparum. Reinfections (N=50 with sufficient DNA for genotyping) and recrudescences (N=3) often grew through high concentrations of desethylamodiaquine, yet all 250 P. falciparum isolates genotyped were Pfcrt 76K, a molecular marker of 4-aminoquinoline susceptibility. One-third (21/64) of microscopy-detectable breakthrough P. falciparum infections had patent gametocytaemia. There was a clear chemoprevention exposure–response relationship evident for desethylamodiaquine, but not for sulphadoxine or pyrimethamine. Conclusions In Nampula, northern Mozambique, amodiaquine had low parasitological efficacy and sulphadoxine and pyrimethamine did not contribute significantly to chemoprevention.