The natural history of chronic hepatitis B virus (HBV) infection is highly variable, ranging from a benign course to one of shortened life expectancy. Liver histology represents an accurate tool for assessing progressive liver disease, and has been used in five recent Phase III clinical trials of the oral nucleoside analogue, lamivudine, 100 mg/day, in patients with chronic hepatitis B. Significant improvements in the Knodell histological activity index (HAI) score were reported with lamivudine, with greater decreases noted after 2 years of therapy, consistent with continued alanine transaminase (ALT) normalisation. Histological data showed that lamivudine therapy can resolve or lessen the progression of fibrosis, and reduce the progression to cirrhosis in patients with chronic hepatitis B. These trials also showed that lamivudine provoked significant enhancement of hepatitis B e antigen (HBeAg) seroconversion compared with placebo, and had a profound effect on serum HBV DNA, resulting in rapid suppression of viraemia. The emergence of variants with a mutation in the YMDD (tyrosine-methionine-aspartate-as-partate) motif did not cause significant worsening of the Knodell HAI score. In conclusion, lamivudine is the first oral antiviral therapy for the treatment of chronic hepatitis B. It reduces significantly the severity of liver disease and reduces progression to cirrhosis. In addition, because lamivudine is well tolerated it represents a viable therapeutic option that may improve the prognosis of patients with chronic hepatitis B. J. Med. Virol. 61:380–385, 2000. © 2000 Wiley-Liss, Inc.