Aims: To determine the long-term response to interferon-α therapy in patients with hepatitis B e antigen-negative chronic hepatitis B, and the factors independently associated with response and survival. Methods: Sixty-three patients with documented hepatitis B e antigen-negative chronic hepatitis B treated with interferon-α for a year were followed-up for a period of 6 years. Results: Sustained biochemical and virological response was seen in 34.91% and 33.33% of patients at 6 and 12 months of follow-up, respectively, and histological improvement in 54.5% of sustained responders compared with non-responders (7.1%, P = 0.004, chi-squared test), at 6 months of follow-up. Multivariate analysis showed that patients with hepatitis B virus-DNA levels at 6 months of treatment <10 000 copies/mL had a low probability of relapse, compared with those with levels >10 000 copies/mL (P = 0.032). Age (>65 years) and hepatitis B virus-DNA level at 6 months of treatment (>10 000 copies/mL) were the independent factors for disease progression and survival (P = 0.041 and P = 0.044 respectively). At 6 years, a sustained response was still present in 19.04% of patients and 4.8% of them had developed anti-HBs. Conclusion: Hepatitis B virus-DNA monitoring by quantitative polymerase chain reaction at 6 months of treatment may allow for early prediction of response to interferon-α, and may serve as an indicator of disease progression in the future.