An increase in the aging population is an impending problem. A large cohort study was carried out to determine the influence of aging and other factors on hepatocarcinogenesis in patients treated with interferon. Biopsy-proven 2547 chronic hepatitis C patients registered at our referral center since 1992 were included. Of these, 2166 were treated with interferon-based therapy. Incidences of hepatocellular carcinoma (HCC) associated with interferon were analyzed by Kaplan-Meier and person-years methods for an average follow-up of 7.5 years. Factors associated with HCC risk were determined by Cox proportional hazard analysis. HCC developed in 177 interferon-treated patients. The risk for HCC depended on age at primary biopsy and increased more than 15-fold after 65 years of age. Even when stratified by stage of fibrosis, the cumulative and annual incidences of HCC were significantly higher in older patients than in younger patients (P < 0.001) at the same stage of fibrosis, except for cirrhosis. Progression of fibrosis over time was significantly accelerated in older patients. The impact of viral eradication on HCC prevention was less significant in older patients than in younger patients. Multivariate analysis confirmed that age, gender, liver fibrosis, liver steatosis, total cholesterol level, fasting blood sugar level, baseline and postinterferon alpha-fetoprotein level, and virological response to interferon were independent risk factors associated with HCC. Aging was the strongest risk factor for a nonvirological response to interferon-based antiviral therapy. Conclusion: Elderly patients are at a higher risk for HCC. Hepatitis C viral eradication had a smaller effect on hepatocarcinogenesis in older patients. Patients should therefore be identified at an earlier age and treatment should be initiated. (HEPATOLOGY 2010;52:518-527) P rimary liver cancer is the third most common cause of cancer mortality worldwide, 1 and hepatocellular carcinoma (HCC) is one of the most frequent primary liver cancers. 2,3 Infection with hepatitis C virus (HCV) is a common cause of chronic hepatitis, which progresses to HCC in many patients. 4 The prevalence of older patients has been increasing in Japan, and this is an impending problem in other countries where viral spread has occurred more recently. 5 The number of Americans older than 65 years is expected to double by the year 2030. 6 In Western Europe, people older than 65 years already constitute 15%-18% of the population 7 ; thus, aging patient who is chronically infected with HCV is Abbreviations: AFP, alpha-fetoprotein; HBc, hepatitis B core; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; NASH, nonalcoholic steatohepatitis; SVR, sustained virological response.