The Plasmodium vivax Duffy Binding Protein (DBP) is the ligand in the major pathway for P. vivax invasion of human reticulocytes, making it an appealing vaccine candidate. Region II of DBP (DBP-RII) is the minimal portion of the ligand that mediates recognition of the Duffy Antigen Receptor for Chemokines (DARC receptor) on the reticulocyte surface and constitutes the primary vaccine target. Analysis of natural variation in the coding sequences of DBP-RII revealed signature evidence for selective pressure driving variation in the residues of the putative receptor-binding site. We hypothesize that anti-DBP immunity in P. vivax infections is strain-specific and hindered by polymorphic residues altering sensitivity to immune antibody inhibition. To comprehend the human IgG response following P. vivax infections we investigated the specificity of IgG in Pursat Province, Western Cambodia. Using ELISAs, we quantified the antibody titer against five variant alleles of DBP-RII. We also sequenced the DBP-RII of the field isolates to determine their relationship to the variant alleles used in the ELISAs. When correlating the IgG titer between the DBP variants a strain-specific immune response was observed in patients with a high antibody titer to DBP-RII_AH as compared to the other variants. This was different from the correlation of high antibody titers between DBP-RII_P and DBP-RII_7.18 (ρ=0.88, p-value<0.0001) and DBP-RII_P and DBP-RII_O (ρ=0.87, p-value<0.0001). There appeared to be little correlation between specific polymorphic residues and IgG titer. Understanding the immune response to the polymorphisms within PvDBP will allow further identification of epitopes to enable the production of a more effective P. vivax vaccine