Background. The Plasmodium vivax Duffy Binding Protein (PvDBP) is a key target of naturally acquired immunity. However, the functional receptor-binding region II of PvDBP (PvDBPII) is highly polymorphic. The natural acquisition of antibodies to different variants of PvDBPII, including AH, O, P and Sal1 alleles, the central region III-V, and P. vivax Erythrocyte Binding Protein region II (PvEBPII) and their associations with risk of clinical P. vivax malaria are not well understood. Methodology. Total IgG and IgG subclasses 1, 2, and 3 that recognize four alleles of PvDBPII (AH, O, P, and Sal1), PvDBPIII-V and region II of PvEBP (PvEBPII) were measured in samples collected from a cohort of Papua New Guinean (PNG) children of aged 1-3 years living in a highly endemic area of PNG. The levels of binding inhibitory antibodies (BIAbs) to PvDBPII (AH, O, and Sal1) were also tested in a subset of children. The association of presence of IgG with age, cumulative exposure (measured as the product of age and malaria infections during follow-up, i.e. molFOB) and prospective risk of clinical malaria were evaluated. Results. Increase in antigen-specific total IgG, IgG1, and IgG3 with age and cumulative exposure was only observed for PvDBPII AH and PvEBPII. High total IgG responders and IgG3 specific responses to the predominant PvDBPII AH allele, were associated with decreased incidence of clinical P. vivax episodes (aIRR=0.56-0.68, P=<0.001-0.021 ). High total IgG and IgG1 to PvEBPII correlated more strongly with protection against clinical vivax malaria compared with those of all PvDBPII variants (aIRR=0.38, P<0.001). Antibodies to PvDBPII AH and PvEBPII showed evidence of an additive effect, with a joint protective association of 70%. The six children with high levels of Binding Inhibitory Antibodies (BIAbs) to PvDBPII and high strain-transcending blocking ability (i.e. >80%) tended to have less clinical diseases (IRR=0.45, P=0.083). Conclusion. Antibodies to the key parasite invasion ligands PvDBPII and PvEBPII are good correlates of protection against P. vivax malaria in PNG. This further strengthens the rationale for inclusion of PvDBPII in a recombinant subunit vaccine for P. vivax malaria and highlights the need for further functional studies to determine the potential of PvEBPII as a component of a subunit vaccine for P. vivax malaria.