Background PD-1, encoded by PDCD1, is highly expressed on virus-specific T cells and plays critical roles in modulating anti-virus immune responses in chronic viral infection. It is unknown, however, whether polymorphisms of the PDCD1 are associated with viral clearance during chronic viral infections. Methodology and principal findings Here, we used the polymerase chain reaction-restriction fragment length polymorphism method to genotype two single nucleotide polymorphisms (SNPs) of PDCD1 in 502 patients with chronic hepatitis B virus (HBV) infection and 359 healthy controls to determine the association between PDCD1 genotypes and serum viral load as well as the risk of chronic infection. Our results showed that although neither the P7209C/T SNP site nor the P8737A/G site was associated with the risk of chronic HBV infection, the P7209T allele in intron 4 is significantly associated with lower viral burden in the blood. Using a luciferase reporter assay, we demonstrated that the P7209T allele creates a negative cis-element for gene transcription. Conclusions and significance Our data provide the first evidence that PDCD1 polymorphisms is a genetic factor in pathogenesis of chronic viral infection and reveal the functional significance of the P7209 SNP of the PDCD1. © Springer Science+Business Media, LLC 2010.