Previous studies with the malaria vaccine RTS,S/AS02A in young children in a malaria endemic area of Mozambique have shown it to have a promising safety profile and to reduce the risk of Plasmodium falciparum infection and disease. In this study, we assessed the antibody responses to the P. falciparum and hepatitis B components of the RTS,S/AS02A vaccine over a 45 months surveillance period in a large phase IIb trial which included 2022 children aged 1–4 years at recruitment. The RTS,S/AS02A vaccine induced high anti-circumsporozoite antibody levels with at least 96% of hildren remaining seropositive during the entire follow-up period. IgG titers decayed over the first 6 months of follow-up to about 25% of the initial level, but still remained 30-fold higher until month 45 compared to controls. Children with higher levels of naturally acquired immunity at baseline, assessed by blood stage indirect fluorescent antibody test, had slightly higher anti-circumsporozoite levels, after adjusting for the effect of age. The TS,S/AS02A vaccine also induced high levels of anti-hepatitis B surface antigen antibodies (seroprotection >97%). RTS,S/AS02A vaccine is immunogenic and induces long-lasting anti-circumsporozoite antibodies, persisting at least 42 months after immunization. These antibodies may play a role in protection against malaria.