Many variations exist in the first 39 nucleotides of the preS2 (pre-S2; 1-39) region of the HBV genome. Based on the similarities of their coding amino acid sequences to those of prototype HBV, they were classified into 3 different types, adr-preS2, adw-preS2 and ayw-preS2. To clarify the meaning of these variabilities in the preS2 region, we studied the HLA class I phenotype of chronic hepatitis B patients having high levels of serum ALT. Our results indicated that in 12 of 14 chronic hepatitis patients infected with HBV type adr-preS2 had HLA-A24 phenotype whereas all of 7 patients infected with either adw- or ayw-preS2 HBV had HLA-A2 phenotype. This strong association between HLA class I phenotype and certain preS2 types of HBV infection was found only in patients with high serum ALT levels but not in patients with almost normal levels of serum ALT. Our results therefore suggest that in the generation of chronic hepatitis B a suitable combination between a fragment of preS2 antigen and HLA class I antigens of the infected host, such as adr-preS2 with HLA-A24 and either adw- or ayw-preS2 with HLA-A2, might be required.