It remains unclear whether sequential assessment of hepatitis B virus (HBV) load during lamivudine therapy can predict the loss of hepatitis B e antigen or emergence of drug-resistant variants. Therefore, a longitudinal study was carried out in 28 consecutive patients with chronic hepatitis B who started lamivudine therapy for a median of 12 months (range, 6–31). HBV DNA copy numbers were determined at 3-month intervals. From month 6 onward, HBV viral load below the detection limit of the PCR was predictive of the loss of envelope antigen (P = 0.043). Continuously detectable HBV DNA during the first 12 months of treatment indicated emergence of drug-resistant variants (P = 0.034). These data suggest that the goal of lamivudine therapy should be complete suppression of serum HBV DNA. J. Med. Virol. 65:659–663, 2001. © 2001 Wiley-Liss, Inc.