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Hepatitis E virus (HEV) is a single-stranded, positive RNA virus. The HEV is the causing agent of hepatitis, with a high prevalence rate in low-income countries due to poor sanitary conditions. It can exhibit acute, continuous, or extrahepatic consequences in immunocompromised individuals such as those undergoing organ transplantation and having HIV infection. HEV infection is either self-limiting (silent), meaning the patient will possibly recover on his own, or symptomatic, causing acute liver injury or fulminant hepatitis, and may eventually cause death. It can also cause chronic hepatitis that can progress to cirrhosis or recovery. Pregnancy-related HEV infection has an incidence rate of 30%. HEV escape from innate immunity, hormonal imbalances, defective monocyte–macrophage function, downregulation of the T-cell-mediated immune system, high cytokine production, nutritional factors, and socioeconomic conditions may play fundamental roles in the prevalence of HEV infection. It is necessary to take particular measures to reduce the incidence burden of HEV infection in high endemic locations.