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Hepatitis E virus (HEV) infection is usually self-limited but may lead to acute hepatitis and rarely to fulminant hepatic failure. Persistent HEV infections have recently been described in organ transplant recipients receiving immunosuppressive medications, suggesting that HEV is controlled by adaptive immune responses. However, only few studies have investigated HEV-specific T-cell responses and immune correlates for the failure to clear HEV infection have not been established so far. We investigated T-cell responses against HEV in 38 subjects including anti-HEV-positive (exposed, n 5 9) and anti-HEV-negative (n 5 10) healthy controls, 12 anti-HEV-positive but HEV RNA-negative organ transplant recipients, and seven transplant recipients with chronic hepatitis E. Proliferation as well as cytokine production of CD41 and CD81 T cells was studied after stimulation with overlapping peptides spanning all proteins encoded by HEV-open reading frame (ORF)2 and HEV-ORF3. We show that (1) strong and multispecific HEV-specific T-cell responses are present in exposed healthy controls, and to a lesser extent also in recovered patients after transplantation; (2) that these responses are absent in patients with chronic hepatitis E but become detectable after viral clearance; and (3) that HEV-specific T-cell responses can be restored in vitro by blocking the PD-1 or CTLA-4 pathways. However, a combination of PD-1 and CTLA-4 blockade had no synergistic effects. We conclude that chronic hepatitis E is associated with impaired HEV-specific T-cell responses and suggest that enhancing adaptive cellular immunity against HEV might prevent persistent HEV infections. (HEPATOLOGY 2012;55:695-708)