Background: Patients with chronic hepatitis B Virus (HBV) infection are at increased risk for hepatocellular carcinoma (HCC). Population-based studies have suggested an increased risk of hepatocellular carcinoma (HCC) in patients with higher levels of HBV-DNA. Therefore, it is possible that anti-viral therapy that reduces HBV-DNA levels may reduce the occurrence of HCC. We examined the clinical and demographic characteristics of HCC cases in patients receiving tenofovir disoproxil fumarate (TDF). Methods: We studied the clinical and demographic characteristics of the 641 patients enrolled in pivotal studies GSUS- 174-0102 and GS-US-174-0103. Results: During the first 288 weeks of studies 102/103, there were 13 cases of HCC. Three cases occurred during the first 48 weeks. 9/13 cases were HBeAg-negative and 3 of these were cirrhotic. 4/13 cases were HBeAg-positive at baseline and 3 of these were cirrhotic. 11/13 cases were male. 2/13 patients had regression of histological cirrhosis on repeat liver biopsies. Among the 13 HCC cases, 5 were genotype (gt)-D, 4 gt-C, 1 gt- B, 1 gt-E, 1 gt-F and 1 unable to genotype. Conclusions: In 288 weeks of TDF therapy, there were only 13 cases of HCC. 3 of the HCC cases were reported within the first 48 weeks of therapy. Despite the small number of cases, HCC surveillance needs to be done in patients on long-time oral antivirals.