Lamivudine is a potent inhibitor of hepatitis B virus (HBV) replication, but its long-term use may be associated with HBV tyrosine-methionine-aspartate-aspartate (YMDD) motif mutation. To examine the clinical features and course after emergence of YMDD mutants, 55 patients who received lamivudine therapy over 104 weeks at our unit were assayed for YMDD mutation(s). Thirty-two of them were found to have the YMDD mutation. They continued lamivudine therapy and were followed up weekly or biweekly if clinically indicated. Thirty (93.7%) of them showed elevation of alanine transaminase (ALT), and 13 (40.6%) experienced acute exacerbation at 4 to 94 weeks (median, 24 weeks) after emergence of the YMDD mutant. The incidence of exacerbation is much higher than 4.3% in patients without the YMDD mutation (P = .003). Compared with patients without exacerbation, patients with exacerbation had a significantly higher serum HBV-DNA level after emergence of the YMDD mutant (P < .005). Before exacerbation, serum HBV-DNA level was rising to its peak, followed by the peaking of ALT (247-2,010 U/L) 1 to 4 weeks later. Three patients developed hepatic decompensation, but then in association with hepatitis B e antigen (HBeAg) seroconversion, recovered. Of the 12 evaluable patients, 8 (75%) showed HBeAg seroconversion, and 3 showed mutant clearance within 1 to 5 months after exacerbation. In contrast, none of the patients without exacerbation showed HBeAg seroconversion (P < .001). These results indicate that acute exacerbations may occur after emergence of the YMDD mutation. The incidence, clinicopathological features, and subsequent course, and possibly the underlying immune mechanisms, are similar to those of wild-type HBV chronic infection. Because severe hepatitis may occur, patients should be followed carefully once the YMDD mutant emerges.