BACKGROUND Given the overlap between envelope and polymerase in the hepatitis B virus (HBV) genome, changes in antigenic sites of the HBV surface antigen may occur as a result of selection of drug-resistance mutations. METHODS Serum HBV-DNA was isolated from 71 patients with chronic hepatitis B receiving anti-HBV drugs for longer than 12 months, 52 of whom were HIV-positive. The reverse transcriptase/envelope gene from each HBV isolate was amplified using a nested polymerase chain reaction (PCR) covering 720 bp (aa 48 to 288), which includes all known nucleos(t)ide analogue resistance mutations in HBV. RESULTS All but 13 patients had received lamivudine. Of the rest, 10 HBV-monoinfected subjects had received adefovir and 3 HBV/HIV-coinfected patients had been treated with tenofovir. Only lamivudine-resistance-associated mutations produced changes in the HBV envelope antigenic sites. Lamivudine resistance mutations were more frequent in HBV genotype A than D (P = 0.014). Contrary to monoinfected individuals, HBV genotype A was the predominant genotype among HBV/HIV-coinfected patients. The triple-HBV mutant rtV173L + rtL180M + rtM204V, which has been shown to produce a diminished hepatitis B surface (HBs) antigen-antibody binding, was found in 3 individuals, all coinfected with HIV and HBV. CONCLUSIONS Circulation of HBV encoding envelope mutations with diminished HBs antigen-antibody binding as result of selection of drug-resistance mutations may occur, particularly in patients infected with HBV genotype A, the most prevalent genotype among HBV/HIV-coinfected patients. Such mutations might represent a public health concern because of the potential risk of transmission of HBV drug- and vaccine-resistant strains.