The response to interferon-alpha treatment of patients with chronic hepatitis B under the current protocol is not satisfactory. The aim of this study was to try an alternative approach to improve treatment outcome. Of 374 HBeAg-positive patients, 127 of them received 5 million units of interferon-alpha thrice weekly for 6 months and constituted the control group, while 247 in the study group received the same dosage but the duration of treatment was tailored. The study protocol provided for continuation of treatment if HBV DNA levels were continuously decreasing. The treatment ended when viral, antigenic and biochemical endpoints were reached or when HBV DNA levels were no longer decreasing. The median length of tailored treatment was 10 (range 6-24) months. The end-of-treatment response rates were 39.3% and 23.6% (P = 0.002), and after 12-month, follow-up, the sustained response rates were 40.5% and 28.3% (P = 0.013) in the study and control groups, respectively. Excluding the patients who dropped out, 228 and 115 completed a median of 40- and 44-month-long follow-up; the long-term response was thus 45.3% and 33.1% (P = 0.014) in the respective groups. Interferon-alpha treatment tailored in length demonstrated significantly increased efficacy in patients with chronic hepatitis B.