The incidence of hepatocellular carcinoma (HCC) is increasing in North America, Europe, and Japan, caused largely by the high rates of chronic hepatitis C virus (HCV) infection. In such individuals, the risk factors for developing HCC are advancing age, male gender, worsening hepatic fibrosis (particularly cirrhosis), and greater degrees of hepatic inflammation. Additional, potentially modifiable risk factors include coinfection with hepatitis B, excessive alcohol use, iron overload, and diabetes/obesity. Thus, approaches to preventing HCC should focus on eradicating HCV infection, responsible for the inflammation and fibrosis, and also on treating or reducing the modifiable risks, such as through hepatitis B vaccination, decreasing alcohol use, phlebotomy for iron overload, and weight control and diabetes prevention. These approaches have yet to be proven effective. Meta-analyses of standard interferon monotherapy trials in patients with HCV-related cirrhosis suggest that interferon has a small but significant effect on reducing HCC risk, particularly in those who achieve a sustained response. Other studies indicate that the reduction in HCC is greatest if a response is achieved before cirrhosis develops. Secondary prevention when HCC has been ablated or resected may be partially effected with interferon treatment or oral polyprenoic acid. No long-term studies of the effect of the currently recommended regimen of peginterferon and ribavirin have been reported, and no current trials include untreated control groups. Studies of maintenance peginterferon therapy in virological nonresponders are under way in the hope of proving that this approach is effective in decreasing the risk of HCC.