We sought to evaluate the long-term results of interferon-alpha (IFN-alpha) therapy in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. Eighty HBeAg-negative naive patients (62 men; mean age, 39.9 years) who received IFN-alpha for 6 months were studied. Alanine aminotransferase normalization with undetectable HBV-DNA by molecular hybridization was accepted as response. All patients but 1 were precirrhotic stage. At the end of treatment, 44 (55%) patients responded, and they were followed for a mean of 59.5 months (range, 18-132). Twenty-seven patients (61.4%) showed recurrence (63% in first year). Responses at 6 months and at the end of the follow-up period 42.5% and 30% (including 7 patients without end treatment response), respectively. Recurrence of HBV replication was not detected after the 2-years follow-up period. Histologic improvement was observed in 83.3% patients with end-of-follow-up response. HBsAg became negative in 4 patients (5%). On multivariate analysis, younger age (P=.04) and lower GGT level (P=.037) were independent factors for prediction of end-of-follow-up response. Nearly half of the patients with HBeAg-negative chronic hepatitis B responds to IFN-alpha at the end of therapy. Despite the high recurrence rates, response continues in about one third of patients after a mean of 59.5 months.