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Background: Plasmodium falciparum merozoite surface protein 5 (PfMSP5) is an attractive blood stage vaccine candidate because it is both exposed to the immune system and well conserved. To evaluate its interest, we investigated the association of anti-PfMSP5 IgG levels, in the context of responses to two other conserved Ags PfMSP1p19 and R23, with protection from clinical episodes of malaria in cross-sectional prospective studies in two different transmission settings. Methods: Ndiop (mesoendemic) and Dielmo (holoendemic) are two Senegalese villages participating in an on-going long-term observational study of natural immunity to malaria. Blood samples were taken before the transmission season (Ndiop) or before peak transmission (Dielmo) and active clinical surveillance was carried out during the ensuing 5.5-month follow-up. IgG responses to recombinant PfMSP5, PfMSP1p19 and R23 were quantified by ELISA in samples from surveys carried out in Dielmo (186 subjects) and Ndiop (221 subjects) in 2002, and Ndiop in 2000 (204 subjects). In addition, 236 sera from the Dielmo and Ndiop-2002 surveys were analyzed for relationships between the magnitude of anti-PfMSP5 response and neutrophil antibody dependent respiratory burst (ADRB) activity. Results: Anti-PfMSP5 antibodies predominantly IgG1 were detected in 60–74% of villagers, with generally higher levels in older age groups. PfMSP5 IgG responses were relatively stable for Ndiop subjects sampled both in 2000 and 2002. ADRB activity correlated with age and anti-PfMSP5 IgG levels. Importantly, PfMSP5 antibody levels were significantly associated with reduced incidence of clinical malaria in all three cohorts. Inclusion of IgG to PfMSP1p19 in the poisson regression model did not substantially modify results. Conclusion: These results indicate that MSP5 is recognized by naturally acquired Ab. The large seroprevalence and association with protection against clinical malaria in two settings with differing transmission conditions and stability over time demonstrated in Ndiop argue for further evaluation of baculovirus PfMSP5 as a vaccine candidate. [ABSTRACT FROM AUTHOR]