Liver cirrhosis is a diffuse chronic liver disease affecting the entire liver. The fibrosis accumulation and distribution in the liver are known to be heterogeneous. "Localized" or "focal" cirrhosis is only anecdotically reported. Acute hepatitis E virus (HEV) infection is uncommon in western countries, especially in temperate climate areas and is very often missed or underdiagnosed. However, it may be responsible of up to 15% of acute-on-chronic liver failure cases. We present the case of a 35-year-old patient with a very uncommon association of Budd-Chiari syndrome secondary to hepatocellular carcinoma (HCC) developed on a non-cirrhotic right liver lobe and secondary biliary cirrhosis of the left liver lobe, that further complicated with acute HEV infection leading to acute-on-chronic liver failure and death.