Hepatitis B viral genotypes influence natural history, with genotype C more likely to develop hepatocellular carcinoma than genotype B, thus influencing the need for intervention. In hepatitis B early antigen (HBeAg)-positive disease, the data with conventional interferon and pegylated interferon (peginterferon) provide compelling evidence that genotype A responds best. The argument for differentiating between genotypes B and C is less clear, but the response in genotype B appears better than in C. Loss of hepatitis B surface antigen (HBsAg) is also most common in genotype A. Patients with genotype A and B should be offered peginterferon as first-line therapy, because it offers potential for HBeAg seroconversion with a finite course of therapy. In HBeAg-negative disease, genotype A again gives the best response, although it is an uncommon genotype here. The response in other genotypes is also good, with 12% of patients losing HBsAg 5 years after treatment. Genotypes may also influence nucleoside resistance mutations and HBsAg loss.