A randomised, multicentre, double-blind, placebo controlled trial was conducted in Chinese patients with chronic hepatitis B to compare the efficacy of once-daily lamivudine and placebo on serum HBV DNA, and to assess the long-term efficacy and safety of lamivudine. Patients received lamivudine 100 mg (n = 322) or placebo (n = 107) once daily for 12 weeks, and were then offered open-label lamivudine treatment for 2 years. Lamivudine therapy resulted in increased hepatitis B e antigen (HBeAg) loss and seroconversion (loss of HBeAg plus the development of antibodies to HBeAg) in patients with high baseline serum alanine aminotransferase (ALT) concentrations. At 2 years, loss of HBeAg was achieved by 27% (38/140), 38% (25/66) and 60% (9/15), and seroconversion was achieved by 17% (24/140), 24% (16/66) and 33% (5/15) of patients with baseline serum alanine aminotransferase (ALT) concentrations of >1 × upper limit of normal (ULN), >2 × ULN and >5 × ULN, respectively. With lamivudine treatment, serum HBV DNA decreased rapidly to very low concentrations and remained low throughout the 2 years of the study. At 1 year, 15% (43/295) of patients in the lamivudine group had developed YMDD (tyrosine-methionine-aspartate-aspartate amino acid motif of HBV polymerase) variant HBV. These patients derived clinical benefit with continued lamivudine therapy, demonstrated by serum HBV DNA and ALT concentrations below baseline, or normal serum ALT concentrations. Lamivudine was well tolerated and an effective once-daily oral therapy for Chinese patients with chronic hepatitis B with viral replication and liver disease. J. Med. Virol. 61:392–397, 2000. © 2000 Wiley-Liss, Inc.