Malaria is one the most serious infectious diseases of humans. Most cases of severe disease are caused by Plasmodium falciparum. After years or repeated exposure, individuals living in endemic areas develop clinical immunity. Naturally acquired immunity targets blood-stage parasites and, as demonstrated by passive transfer studies, requires antibody responses. Despite the key role that antibodies play in protection, the specific targets of immunity are unknown. The merozoite surface consists of GPI-anchored and extrinsically-associated proteins lacking transmembrane domains. This surface coat allows invasion of the parasite into the red blood cell. The erythrocyte binding-like protein family functions after initial merozoite interaction by binding to receptors on the red blood cell via the Duffy binding-like (DBL) domain. Two merozoite surface proteins DBL1 and -2 (PfMSPDBL1 and PfMSPDBL2) have been recently identified. They are extrinsically associated with the merozoite and have a DBL domain, suggesting they play a role in parasite invasion. To determine if these proteins are targets of naturally acquired immunity, antibody responses to PfMSPDBL1 and PfMSPDBL2 were investigated in a treatment-re-infection study of 206 semi-immune children aged 4-14 year-old from a hyperendemic area of Papua New Guinea. Antibody titres to both PfMSPDBL1 (high (H) vs. low (L) responders: Incidence rate ratio (IRR) = 0.29, p < 0.001) and PfMSPDBL2 (H vs. L: IRR = 0.32, p < 0.001) showed strong associations with protection against P. falciparum clinical episodes. Adjusting for difference age, location and overall immune status did change the strength of these associations. When associations with time to first infection were analysed, antibodies levels against both PfMSPDBL1 and PfMSPDBL2 were also found to be associated with protection from high-density (P. falciparum> 5000) infections but not from lower density infections. Together these results indicate that PfMSPDBL1 and PfMSPDBL2 are important targets of protective immunity and constitute promising vaccine candidates.