To determine whether a dramatic decrease in hepatitis B virus (HBV) DNA levels within the first months of lamivudine therapy can predict the emergence of YMDD variants in patients with chronic hepatitis B, quantitative testing was done every 3 months on serum samples from 35 patients who were treated with lamivudine for >1 year. The decline in HBV DNA levels from baseline to month 3 was higher in 22 responders than in 13 nonresponders (mean+/-SD, 4.16+/-1.06 vs. 2.88+/-1.77 log(10) copies; P=.002), whereas no differences were observed in patients with and without YMDD variants at 1 year of therapy. At 3 months, HBV DNA was undetectable in 77% of the responders, whereas, after 1 year, it was undetectable in 23% of nonresponders, 40% of patients with YMDD variants, and 74% of those without variants. Therefore, quantitative HBV DNA testing is very useful in deciding whether to continue therapy, because of the low likelihood of response in patients who remain HBV DNA positive at month 3 of treatment.