High viral load is an independent risk factor for development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). Antiviral therapy can reduce but not eliminate the risk of HCC. The aim of this study was to identify the risk factors for HCC development in CHB patients during antiviral therapy.CHB patients with HBV DNA level ≥10 copies/mL, with or without compensated cirrhosis receiving adefovir were followed up every 6 months for 10 years (2004-2014). The primary endpoint was the development of HCC. The cumulative incidence and risk factors of HCC were evaluated by the Kaplan-Meier method and multivariate Cox proportional hazards models.At baseline, 28 of the 120 patients (23.3%) were cirrhotic. One patient developed HCC within 1 year, and therefore 119 patients were analyzed. At the end-point of follow-up, 59.7% (71/119) patients achieved virological remission (VR). Overall, 16 patients developed HCC, giving a 10-year cumulative incidence of 15.73%. Multivariate analysis showed that cirrhosis at baseline and failure to achieve VR were significant risk factors for HCC. The 10-year incidence of HCC was significantly higher in cirrhotic than noncirrhotic patients (43.16% vs. 7.05%, P < .0001). For cirrhotic patients, the 10-year incidence of HCC was significantly higher in patients without VR than those with VR (62.24% vs. 27.78%, P = .0139).Cirrhosis at baseline and failure to achieve VR during antiviral therapy were significant risk factors for HCC development in CHB patients. Effective viral suppression is necessary to reduce HCC development in cirrhotic CHB patients.