With phylogenetic analysis of hepatitis B virus (HBV) isolates, eight different genotypes (A to H) have been recognized worldwide. The impact of HBV genotypes on the clinical aspects of HBV infection in Taiwan, including the clinical outcome of chronic infection and therapeutic response to antiviral treatments, has been clarified. Our data showed that genotypes B and C are the predominant HBV strains in Taiwan, and genotype C is associated with more severe liver disease including cirrhosis and hepatocellular carcinoma (HCC), whereas genotype B is associated with the development of HCC in young noncirrhotic patients. Serologically, genotype C tends to have a higher frequency of hepatitis B e antigen (HBeAg) positivity and a higher serum HBV DNA level than genotype B. In addition, genotype C patients, compared to genotype B patients, have a delayed HBeAg seroconversion in the immune clearance phase of chronic HBV infection. Virologically, genotype C bears a higher frequency of basal core promoter mutation than genotype B. Our recent data further indicated that patients with basal core promoter mutation are significantly more associated with the development of HCC than those without, which applies to both genotypes B and C. In addition, the prevalence of basal core promoter mutation in young HCC patients is comparable to older HCC patients but is significantly higher than that in age-matched inactive carriers, irrespective of genotypes. Although superinfection of HBV on hepatitis B carriers indeed occurs in Taiwan, it is rarely associated with acute exacerbations. As to the response to antiviral treatments, genotype C is associated with a lower response rate to interferon therapy compared to genotype B. In addition, genotype B seems to have a better virological response to lamivudine as compared to genotype C, but both genotypes have a similar risk in the development of lamivudine resistance. These lines of evidence highlight the remarkable differences in the clinical and virological characteristics between Taiwanese patients infected with different genotypes. In conclusion, pathogenic and therapeutic differences do exist among HBV genotypes in Taiwan, and determining the genotype in patients with chronic HBV infection would help gain further information in anthropologic, clinical, virological and prognostic investigations.