Chronic hepatitis E virus (HEV) infection may occur in immunocompromised patients. Previous studies report that different immunosuppressive agents interfere with viral replication. However, the role of TNFα in HEV infection is currently unknown. Here, we describe a case of severe exacerbation of a chronic HEV infection in a patient undergoing treatment with a TNFα-inhibitor for psoriatic arthritis despite potent anti-HEV T-cell responses. We used state-of-the-art HEV cell culture methods to test antiviral effects of different drugs and a cytokine release assay to assess HEV specific T cell immunity. In addition standard tools of our diagnostics laboratory were employed. In vitro data confirmed inhibition of HEV replication by TNFα, which could be abolished by addition of TNFα inhibitors. Thus, TNFα may play a critical role in the control of HEV replication. We therefore recommend exclusion of HEV infection prior to initiation of TNFα-inhibitor therapy.