Chronic hepatitis B is a leading cause of hepatocellular carcinoma globally. Liver cirrhosis, high viral load, positive hepatitis B e antigen, and elevated serum alanine aminotransferase are potentially modifiable risk factors for hepatocellular carcinoma with antiviral therapy. Patients achieving surrogate treatment end points (eg, histologic response and biochemical response) have reduced risk of hepatocellular carcinoma and liver-related complications. Animal studies, observational studies, and a few meta-analyses have shown the protective effect of antiviral therapy on hepatocellular carcinoma. On the other hand, there are few randomized controlled trials using hepatocellular carcinoma as the primary end point. In addition, the cost-effectiveness and long-term safety of antiviral therapy remain important unanswered questions.