A PCR restriction fragment length polymorphism assay was used to analyse single-nucleotide polymorphisms in the tumour necrosis factor (TNF)-alpha and TNF-beta genes of 56 patients with chronic severe hepatitis B virus (HBV) infection, 71 patients who either had chronic mild HBV infection or who were asymptomatic carriers, and 90 healthy controls. The serum TNF-alpha concentrations in patients with chronic severe HBV infection were compared to those of 30 healthy controls by radioimmunoassay. The frequencies of the TNF1/2 genotype and the TNF2 allele were greater in patients with chronic severe HBV infection than in healthy controls (25% vs. 11.1%, p 0.015; 12.5% vs. 5.6%, p 0.036, respectively) and patients with chronic mild HBV infection and asymptomatic carriers (25% vs. 8.8%, p 0.011; 12.5% vs. 4.2%, p 0.015, respectively). Heterozygotes carrying the TNF2 allele had higher levels of serum TNF-alpha than homozygotes for the wild-type allele among all patients with chronic severe HBV infection (p <0.01). The genotype distribution and allele frequency of TNF-beta were similar for patients with chronic severe HBV infection and healthy controls, but the frequency of the TNF-beta*2/2 genotype in patients with chronic mild HBV infection and asymptomatic controls was lower than for healthy controls (9.9% vs. 22.4%, p 0.043) or patients with chronic severe HBV infection (9.9% vs. 26.8%, p 0.043), although this was not significant after correction for multiple testing. It was concluded that TNF-alpha gene polymorphisms may play an important role as a host factor in the progression of HBV infection.