The long-term effect of interferon alfa (IFN-α) in Chinese patients with chronic hepatitis B infection is unknown. A total of 411 chronic hepatitis B patients (208 treated with IFN-α and 203 as control) were followed up for hepatitis B serology and the development of hepatoma and other cirrhosis-related complications. The hepatitis B e antigen (HBeAg) seroconversion rate in the IFN-α–treated group, though significantly greater at 6 and 24 months, was comparable with the control group on subsequent follow-up, irrespective of pretreatment alanine transaminase (ALT) levels. HBeAg seroreversion rate was higher in the IFN-α group compared with the control group (21.1% vs. 2.2%; P = .001). Loss of hepatitis B surface antigen (HBsAg) occurred in 2.4% of the IFN-α–treated patients and 0.49% of the control patients (P = NS). Around 90% of the anti-HBe–positive patients in both groups were still hepatitis B virus (HBV)-DNA–positive by polymerase chain reaction (PCR) assay. Two patients suffered from hepatic reactivation during the course of treatment. Nine (4.3%) patients in the IFN-α group and 2 (1.0%) in the control group developed complications of cirrhosis and hepatoma (P = .062). In Chinese HBsAg carriers, IFN-α was of no long-term benefit in inducing HBeAg seroconversion or in the prevention of hepatoma and other cirrhosis-related complications.