The effect of interferon (IFN) on hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) has not been fully investigated in Chinese patients. We enrolled 58 HBeAg-negative CHB Chinese patients with hepatitis B viremia in Taiwan to evaluate the response to IFN. 30 patients received recombinant IFN 5 million units 3 times weekly for 6–10 months, and 28 patients who refused IFN treatment served as controls. Rates of virological response and biochemical response were higher in the treated group at the end of treatment (57% vs 18%, P=0.006, and 73% vs 29%, P=0.002, respectively). Both effects were superior in the treated group at 6 months after IFN withdrawal (virological: 30% vs 7%, P=0.06; biochemical: 47% vs 7%, P=0.002). Improvement of liver histological activities with persistently biochemical response was found in 65% of the treated patients. After a mean of 32 months’ follow-up, virological response was rarely maintained (17% vs 4%, P=0.228) but biochemical response was better in the treated group (27% vs 4%, P=0.039). None of the treated patients but five controls developed severe complications of CHB during the follow-up period. A larger total IFN dosage or a younger age (≤ 40 years) were associated with ‘sustained’ virological response. Younger age and higher baseline alanine transaminase values (≥ 120 Ul–1) were related to ‘sustained’ biochemical response.