Markedly elevated alpha-fetoprotein levels in the range of >1,000 ng/mL are highly suspicious for the presence of hepatocellular carcinoma. This report describes three patients with cirrhosis and replicating hepatitis B virus infection who presented with initial serum alpha-fetoprotein levels of >1,000 ng/mL without clear evidence of hepatocellular carcinoma based on multiple abdominal imaging studies. Initiation of lamivudine treatment led to rapid and dramatic reductions in the alpha-fetoprotein level to the normal range within 12 weeks in one patient and by >1 log at 7 and 16 weeks in the other two patients. One of the three patients previously developed lamivudine resistance, and discontinuation of lamivudine led to a severe flare of hepatitis B before lamivudine treatment was restarted. During a follow-up period of 14 to 36 months, all three patients maintained stable alpha-fetoprotein levels and had no signs of hepatocellular carcinoma demonstrated by serial abdominal imaging studies. The dramatic decrease in the alpha-fetoprotein levels in these patients is unlikely to be a spontaneous event but is possibly due to suppression of viral replication and associated hepatic inflammatory activities by lamivudine. These observations may be helpful in the diagnostic evaluation and management of patients with markedly elevated alpha-fetoprotein levels and chronic hepatitis B-related cirrhosis.