Hepatitis B virus (HBV) with various mutations has been reported. The frequency of the natural occurrence of such variants and whether the heterogeneity of these genomic regions correlates with a specific serologic pattern of concurrent hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs) were investigated. We analyzed the perS/S regions of HBV in six asymptomatic HBV carriers who were seropositive for both HBsAg and anti-HBs (group A), four hepatocellular carcinoma (HCC) patients with concurrent HBsAg and anti-HBs (group B), and five asymptomatic HBV carriers without anti-HBs as controls (group C). PreS/S regions of HBV-DNA were amplified by polymerase chain reaction (PCR), cloned, and sequenced. The results showed that, in some of the samples, a few deletions and numerous point mutations were presented in preS/S regions. One of the HBV carriers with anti-HBs (group A) and an HCC patient with anti-HBs (group B) had point mutations in the "a" determinant, resulting in conversion from Ile-126 of wild-type to Asn-126. The patients with anti-HBs (groups A and B) had a significantly greater divergence rate of amino acid for the preS/S gene compared with controls. Our results suggested that the HBV mutants observed in the preS/S gene may have led to changes in the immunogenicity of the viral particles, and thus influence the viral behavior and clinical course. Therefore, some HBV patients with concurrent HBsAg and anti-HBs may be HBV S mutants.