The interaction between the Plasmodium vivax merozoite Duffy binding protein region II (DBPII) and the human erythrocyte Duffy antigen leads to infection. Highly polymorphic regions of this protein may have arisen as a mechanism to avoid host immunity. To examine whether immunity to P. vivax is directed against these polymorphic regions of DBPII, age-associated changes in the frequency of specific DBPII alleles among 358 P. vivax-positive Papua New Guineans were examined. Although the overall number and diversity of DBPII haplotypes simultaneously infecting an individual decreased with increasing age, only certain alleles at particular loci declined in frequency, indicating preferential immune selection against these alleles. One such polymorphic locus formed part of a B cell epitope, and antibodies from exposed individuals differentially recognized alleles at this locus. Therefore, acquisition of strain-specific age-acquired immunity is partially directed against polymorphic motifs within P. vivax DBPII, suggesting that these polymorphisms are maintained and likely arose under immune pressure in the host.