Introduction and Objectives: Hepatitis E virus (HEV) is a zoonosis associated with chronic hepatitis and cirrhosis in immunocompromised patients. Robust animal models are needed for a better understanding of the pathogenesis of chronic HEV infection. To this aim, we developed a new pig model to characterize the HEV genetic changes associated with chronicity, and the impact of HEV infection on the host innate immune responses. Material and Methods: Twenty piglets were separated into control (n=5), immunocompromised (IC, n=5) and immunocompromised and HEV infected group (IC+HEV, n=10). Pigs were intravenously infected with HEV-3 after two weeks of treatment with immunosuppressive drugs used in kidney transplant recipients (tacrolimus, mycophenolic acid and prednisolone). Pigs were treated and monitored weekly until 11 weeks post infection (wpi). Tacrolimus through concentrations were monitored by HPLCMS/MS (Waters). HEV infection and viral diversity were followed-up by qRT-PCR and NGS analysis (MiSeq, Illumina), respectively. Host innate immune responses were followed-up using DNA array (Fluidigm). Results, Discussion and Conclusion: A unique and relevant animal model of chronic HEV infection was successfully established where 9/10 pigs progressed to chronicity (> 8 wpi) with an inflammatory infiltrate in the liver. Extrahepatic replication in the colon and a unique HEV compartmentalization between sera and feces were observed. One mutation, Y590C (ORF1), was detected (>20%) during the chronic phase in the feces of 6/9 pigs, but not in sera nor in the initial inoculum. Three other mutations were detected (>50%) during the chronic phase: H662L (ORF1, feces), V871A (ORF1, sera) and A639V (ORF2, sera), each in one pig. A pro-inflammatory response and activation of the host innate immune responses (PRR, NF-kB and type I IFN pathways) was observed in blood at acute (4 wpi) and chronic (10 wpi) phases of HEV infection. This systemic inflammation during chronic hepatitis E could be associated with disease progression and/or extrahepatic replication. Contrary, a down-regulation of these pathways was observed in the liver. This suggested a possible inhibition of the host innate immune responses induced by HEV replication. This model could contribute to better understand the pathogenesis of chronic HEV infection and the development of effective therapies.