Hepatitis E virus genotype 3 infections are normally asymptomatic in immunocompetent individuals. Symptomatic cases of acute icteric hepatitis E are seldom observed among women, younger men and children but are particularly seen in middle-aged/elderly men. We report a case of severe acute hepatitis E caused by genotype 3 in an immunocompetent 40-year-old woman that required prolonged hospitalization. Her medical history included an autoimmune background, namely atrophic gastritis and Graves’ disease. She presented an extensive hepatic necrosis as revealed by the high levels of aminotransferases (ALT 4893 U/L; AST 3138 U/L). She showed also a coagulation disorder (prothrombin time; INR = 1.33). Serological markers for hepatitis viruses A, B and C were negative but serum was positive for hepatitis E virus RNA. Sequencing and phylogenetic analysis revealed that the hepatitis E virus strain belonged to subgenotype 3a. This is suggestive of an association between the severe acute hepatitis E virus genotype 3 infection and the autoimmune background.