Cytokine gene polymorphisms influence the severity of infectious diseases of viral and parasitic origin. Interferon alpha (IFN-alpha) is known to be involved in the defence against hepatitis B. The promoter of the IFN-alpha-2 gene was investigated for mutations in 344 hepatitis B virus (HBV)-infected Vietnamese patients and 293 uninfected Vietnamese. We found a deletion in the promoter, which was present significantly more frequently in HBV-infected patients than in control individuals; 20% of the healthy, whereas 35% of the HBV-infected cohort carries this deletion (P<0.001). Reporter gene assays showed that a construct with the deletion had a lower level of transcription in comparison to the wild type (P=0.011). These findings indicate that the deletion in the promoter of the IFN-alpha-2 gene reduces the transcription of this gene in vitro. This reduction could explain the individually different interferon levels in humans and could also be one cause of susceptibility to hepatitis B.