RTS,S/AS02A is a pre-erythrocytic stage malaria vaccine that provides partial protection against infection in malaria-naive adult volunteers and hyperimmune adults. A previous report showed that this vaccine reduced risk of clinical malaria, delayed time to new infection, and reduced episodes of severe malaria over 6 months in African children. An important remaining issue is the durability of protection against clinical disease in these children. We did a randomised, controlled, phase IIb trial of RTS,S/AS02A given at 0, 1, and 2 months in 2022 Mozambican children aged 1–4 years. We previously determined vaccine efficacy (VE) against clinical malaria in a double-blind phase that included study months 2·5–8·5 (VE 2·5–8·5). We now report VE in a single-blind phase up to month 21 (VE 8·5–21). The primary endpoint was time to first or only clinical episode of Plasmodium falciparum malaria (axillary temperature ⩾37·5°C and P falciparum asexual parasitaemia >2500 per μL) detected through a passive case detection system. We also determined VE for other case definitions and for episodes of severe malaria. This study is registered with the ClinicalTrials.gov identifier NCT00197041. During the single-blind phase, VE (8·5–21) was 28·9% (95% CI 8·4–44·8; p=0·008). At month 21, prevalence of P falciparum infection was 29% lower in the RTS,S/AS02A group than in the control (p=0·017). Considering the entire study period, VE (2·5–21) was 35·3% (95% CI 21·6–46·6; p<0·0001) and VE (2·5–21) for severe malaria was 48·6% (95% CI 12·3–71·0; p=0·02). These results show that RTS,S/AS02A confers partial protection in African children aged 1–4 years living in rural endemic areas against a range of clinical disease caused by P falciparum for at least 18 months, and confirm the potential of malaria vaccines to become credible control tools for public-health use.