Hepatitis E virus (HEV) is associated with chronic hepatitis and cirrhosis in immunocompromised patients1. Chronic HEV pathogenesis remains unknow. 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. Twenty piglets were separated into control (n=5), immunocompromised (n=5) and immunocompromisedinfected group (IC+HEV, n=10). Pigs were HEV-3 infected after two weeks of treatment with immunosuppressive drugs (tacrolimus, mycophenolic acid and prednisolone). Pigs were treated and monitored weekly until 11 weeks post infection (wpi). HEV infection and viral diversity were followed-up by qRT-PCR and NGS analysis, respectively. Host innate immune responses were followed-up using DNA array. A unique and relevant animal model of chronic HEV infection was successfully established, where 9/10 pigs progressed to chronicity (> 8 wpi) with inflammatory infiltrates in the liver. Extrahepatic replication in the colon and a HEV compartmentalization between sera and feces were observed. 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. During the chronic phase of HEV infection, host innate immune responses (PRR, NF-kB and type I IFN pathways) were activated in the blood but were down regulated in the liver. This suggested a possible inhibition of the host innate immune responses induced by HEV replication. This model could contribute to a better understanding of the pathogenesis of chronic HEV infection and the development of effective therapies.