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Aim: To investigate the serovirological prevalence and clinical features of hepatitis E virus (HEV) infection in end-stage renal failure patients and in the healthy population., Methods: HEV infection is a viral disease that can cause sporadic and epidemic hepatitis. Previous studies unexpectedly showed a high prevalence of HEV antibodies in immunosuppressed subjects, including hemodialysis (HD) patients and patients who had undergone kidney transplant. A cohort/case-control study was carried out from January 2012 to August 2013 in two hospitals in southern Italy (Foggia and S. Giovanni Rotondo, Apulia). The seroprevalence of HEV was determined in 801 subjects; 231 HD patients, 120 renal transplant recipients, and 450 health individuals. All HD patients and the recipients of renal transplants were attending the Departments of Nephrology and Dialysis at two hospitals located in Southern Italy, and were included progressively in this study. Serum samples were tested for HEV antibodies (IgG/IgM); in the case of positivity they were confirmed by a Western blot assay and were also tested for HEV-RNA, and the HEV genotypes were determined., Results: A total of 30/801 (3.7%) patients were positive for anti-HEV Ig (IgG and/or IgM) and by Western blot. The healthy population presented with a prevalence of 2.7%, HD patients had a prevalence of 6.0%, and transplant recipients had a prevalence of 3.3%. The overall combined HEV-positive prevalence in the two groups with chronic renal failure was 5.1%. The rates of exposure to HEV (positivity of HEV-IgG/M in the early samples) were lower in the healthy controls, but the difference among the three groups was not statistically significant (P > 0.05). Positivity for anti-HEV/IgM was detected in 4/30 (13.33%) anti-HEV Ig positive individuals, in 2/14 HD patients, in 1/4 transplant individuals, and in 1/12 of the healthy population. The relative risk of being HEV-IgM-positive was significantly higher among transplant recipients compared to the other two groups (OR = 65.4, 95%CI: 7.2-592.7, P < 0.001), but the subjects with HEV-IgM positivity were numerically too few to calculate a significant difference. No patient presented with chronic hepatitis from HEV infection alone., Conclusion: This study indicated a higher, but not significant, circulation of HEV in hemodialysis patients vs the healthy population. Chronic hepatitis due to the HEV virus was not observed.