Currently no therapy is given to patients with chronic hepatitis B virus (HBV) infection who are HBeAg positive with normal alanine aminotransferase (ALT) levels. Steroid priming has been shown to enhance T-helper-1 (Th-1) cell response. Lamivudine may restore immunologic competence against HBV by causing a sudden decline in the level of the virus. We examined the efficacy of lamivudine pulse therapy on the seroconversion from HBeAg to anti-HBe. This was a prospective single-blinded trial including 27 patients with chronic hepatitis B, HBeAg positive with ALT < or =1.5 times upper limit of normal (ULN). Lamivudine was administered initially for 4 weeks, then stopped for 2 weeks and later restarted and continued till 3 months after seroconversion or completion of 2 years of therapy. Twenty-six patients completed the study. Lamivudine withdrawal led to a rise in ALT levels above the ULN in 11 (42.3%) patients at 6 weeks; seven of them (63.6%) lost HBeAg compared with only two of the 15 patients (13.3%), in whom ALT levels did not rise (P = 0.011). As one patient showed a relapse, a total of eight (31%) patients responded to lamivudine pulse therapy over a mean period of 17.3 +/- 4.5 months. Responders had a higher serum albumin (P < 0.05), a lower fibrosis score (P < 0.05), and a relatively high baseline serum ALT levels (P = 0.024) than the nonresponders. YMDD mutations developed in three patients and none responded. No patient developed hepatic decompensation. Hence lamivudine pulse therapy has potential in converting HBeAg-positive, 'not-treat-worthy' (ALT < 1.5 ULN) patients to treat-worthy (ALT > 1.5 ULN) in 42%, with sustained HBeAg and HBV DNA loss in 31% patients. The effects are possibly because of a combination of antiviral and immunomodulating activities of lamivudine.