Hepatitis E virus (HEV) infection is a frequent cause of acute viral hepatitis. Immunocompromised patients, especially those under anti-CD20 regimens, are prone to chronic or treatment-resistant courses of hepatitis E. We report a case of chronic HEV infection in a 36-year-old man with a history of thrombotic thrombocytopenic purpura treated with rituximab 6 months ago, who presented with new-onset painless jaundice and malaise. Laboratory tests and imaging revealed signs of inflammation and hepatic dysfunction. Due to initial suspicion of autoimmune hepatitis, corticosteroid therapy was started. However, liver biopsy and positive HEV RNA value redefined the diagnosis. Serology tests revealed initially acute infection, which later progressed to chronic hepatitis E infection. Treatment with ribavirin, along with supportive care, achieved significant clinical and laboratory improvement, resolving jaundice, restoring normal transaminase and suppressing HEV RNA values. Further review of the literature highlights the impact of immunosuppression caused by anti-CD20 therapies on HEV infection, as well as the challenges in both treatment and achieving sustained virus clearance in such patients. Moreover, this report underlines the importance of HEV screening in patients with hepatitis who have undergone anti-CD20 therapies, shedding light on a situation that is not well described in the literature and should not be overlooked, even in developed countries.