Background: chronic infection with hepatitis B virus (HBV) is a major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). Programmed death-1 (PD-1) has been involved in regulating immune responses to viral infections and tumors and has a critical role in HBV infection. Objectives: to investigate the effect of PD1 (+8669 G/A) single-nucleotide polymorphism (SNP) on disease susceptibility and progression of chronic HBV infection in Egyptian patients. Methodology: Blood samples were taken from 70 patients with confirmed chronic hepatitis B (CHB), HBV-related liver cirrhosis (LC) or HCC on top of HBV infection and 25 healthy controls. Genotyping of PD1 (+8669 G/A) polymorphism was studied using bidirectional PCR amplification of specific alleles (Bi-PASA). Results: A significantly higher frequency of PD-1 (+8669 G/A) AA genotype and A allele was found in CHB group (36.8 %) and LC group (21.7%) compared to control group (0.0%) (P< 0.05). On the other hand, the GG genotype and G allele were over represented in healthy controls (72.7%) than CHB group (52.6%) and LC group (47.8%). In assessing the risk of susceptibility to infection with HBV, The G allele was significantly predominant in healthy subjects compared to hepatitis B patients (89.4% versus 68.5%) (P< 0.05). G allele was markedly increased with disease progression to HCC (P = 0.006). Conclusion: Our study suggested that PD1 (+8669) polymorphism has significantly implicated in the disease susceptibility with AA genotype and A allele as a predisposing and the GG genotype and G allele as a preventive factors for chronic HBV infection. Also this study revealed a significant effect of the PD1 (+8669) polymorphism in the progression to HCC in hepatitis B patients.