OBJECTIVE: Cytokines play a key role in the regulation of the immune response. The maximal capacity of cytokine production varies among individuals and correlates with the polymorphism in the cytokine gene promoters. The aim of this study was to characterize gene polymorphism in patients with chronic hepatitis B virus (HBV) infection and to determine the different patterns in patient subgroups. METHODS: The study population consisted of 77 patients with chronic HBV infection (23 low-level HBV replicative carriers, 23 compensated high-level HBV replicative carriers, 21 decompensated liver transplant candidates, and 10 patients with documented hepatocellular carcinoma). The genetic profile of five cytokines was analyzed by polymerase chain reaction-sequence-specific primer (SSP), and subjects were genotyped as high or low producers of tumor necrosis factor-α and interleukin (IL)-6, and as high, intermediate, or low producers of transforming growth factor-β1, interferon (IFN)-γ, and IL-10 based on single nucleotide substitutions. The control group included 10 healthy individuals who recovered from HBV infection and 48 healthy controls. RESULTS: A highly statistically significant difference in the distribution of the IFN-γ gene polymorphism (at position +879) was observed between patients with chronic HBV infection and controls. The majority of the patients (65.2%) exhibited the potential to produce low levels of IFN-γ (A/A genotype) compared with 37.5% of the control group (p = 0.003). Healthy individuals who recovered from HBV infection had a similar distribution of IFN-γ gene polymorphism as the healthy controls. No statistically significant difference in IFN-γ production was found between patients with low- and high-level HBV replication and between compensated and decompensated patients. There was also no statistically significant difference in the genetic ability to produce tumor necrosis factor-α (at position -308), IL-6 (at position -174), IL-10 (at position -1082, -819, and -592), and transforming growth factor-β1 (at position + 10 and +25). CONCLUSION: These findings suggest an association between the genetic ability to produce low levels of IFN-γ and the susceptibility to develop chronic HBV infection.