Accumulated evidence indicated that hepatitis B virus genotype G (HBV/G) is present exclusively in coinfection with other HBV genotypes. In Mexico, HBV/G from 6 men who had sex with men were coinfected with HBV/H. Phylogenetically complete genomes of the 6 Mexican HBV/G strains were closely related to previous ones from the US/Europe. Using uPA/SCID mice with human hepatocytes, monoinfection with HBV/G did not result in detectable HBV DNA in serum, whereas superinfection with HBV/G at week 10 inoculated HBV/H when HBV/H DNA was elevated to >10(7) copies/mL has enhanced the replication of HBV/G. The HBV/G was enhanced in another 3 inoculated with a serum passage containing HBV/G with a trace of HBV/H. Coinfection of mice with HBV/G and H induced fibrosis in the liver. In conclusion, the replication of HBV/G can be enhanced remarkably when it is coinfected with HBV/H. Coinfection with HBV/G may be directly cytopathic in immunosuppressive conditions.