Hepatocellular carcinoma (HCC) is currently a very common malignancy and its incidence is increasing, both in Japan and the USA. Persistent hepatitis C virus (HCV) infection is a major risk factor for the development of HCC. A number of large-scale retrospective cohort studies have demonstrated that interferon therapy reduces the incidence of HCC not only in sustained virological responders but also in transient biochemical responders without the elimination of HCV. We also demonstrated that retreatment with interferon at certain intervals reduced the incidence of HCC in patients with chronic hepatitis C, even if eradication of HCV was not achieved by retreatment. We cannot, however, explain how a transient normalization of serum alanine aminotransferase levels induced by a maximum 6 months of interferon treatment reduces the incidence of HCC during the progression of chronic hepatitis to cirrhosis or HCC, which requires dozens of years. In this article, we discuss how interferon treatment might reduce the incidence of HCC even in transient biochemical responders, especially in view of antiproliferative or antioxidative activity of interferon-alpha.