Background&Aims: Chronic Hepatitis B with high risk for hepatocellular carcinoma (HCC) remains a major challenge, worldwide. Although many HCC cases are driven by hepatitis and liver cirrhosis, a subset of patients develops HCC in the absence of advanced liver disease, indicating the oncogenic potential of Hepatitis B Virus (HBV). We investigated the role of HBV-transcripts and proteins on HCC development in the absence of inflammation in HBV-transgenic mice. MethodsHBV-transgenic mice replicating HBV and expressing all HBV proteins from a single integrated 1.3-fold HBV genome in presence or absence of wildtype HBx (HBV1.3/HBVxfs) were analyzed. Flow cytometry, molecular, histological and in vitro analyses using human cell lines were performed. Hepatocyte-specific Stat3- and Socs3-knockout was analyzed in HBV1.3 mice. Results∼38% of HBV1.3 mice developed liver tumors. Protein expression patterns, histology and mutational landscape analyses indicated that tumors resembled human HCC. HBV1.3 mice showed no signs of active hepatitis up to the time-point of HCC development but STAT3-activation. HBV-RNAs covering HBx sequence, 3.5kb HBV-RNA and HBx-protein were detected in HCC tissue. Interestingly, HBVxfs mice expressing all HBV proteins but a C-terminally truncated HBx (without the ability to bind DDB1) showed reduced signs of DNA damage response and had a significantly reduced HCC incidence. Importantly, intercrossing HBV1.3 mice with a hepatocyte-specific STAT3-knockout abrogated HCC development. ConclusionExpression of HBV-proteins is sufficient to cause HCC in the absence of detectable inflammation. This indicates the oncogenic potential of HBV and in particular HBx. In our model, HBV-driven HCC was STAT3-dependent. Our study highlights the immediate oncogenic potential of HBV, challenging the notion of a benign highly replicative phase of HBV infection and indicating the necessity for an HBV “cure”. Impact and implicationsAlthough most HCC cases in chronically HBV infected patients occur after a sequence of liver damage and fibrosis, a subset of patients develop HCC without any signs of advanced liver damage. We demonstrate that the expression of all viral transcripts in HBV-transgenic mice suffices to induce HCC development independent of inflammation and fibrosis. These data indicate the direct oncogenic effects of HBV and emphasize the notion of early antiviral treatment in the “immune-tolerant” phase (HBeAg positive chronic HBV infection).