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Hepatitis E virus (HEV) is a leading cause of acute viral hepatitis in several developing countries. Information on cellular immune responses during acute hepatitis E is limited. We therefore studied peripheral blood mononuclear cells (PBMCs) from patients with acute hepatitis E and healthy adult subjects who lacked anti-HEV antibodies for enumeration of various T-cell subsets using flow cytometry and to assess HEV-specific T effector cell responses using interferon-gamma ELISPOT assays. The patients showed increased numbers of CD8+ cells and CD4+CD8+ cells compared with healthy controls. In addition, the proportion of PBMCs that produced interferon-gamma in response to recombinant HEV open reading frame (ORF) 2 and ORF 3 proteins were found to be higher in patients than in healthy controls. Using pools of 15-mer overlapping peptides corresponding to these recombinant proteins, the immunodominant regions in these proteins for interferon-gamma-producing cells were mapped to regions corresponding to amino acids 181–249 and 301–489 of HEV ORF2 protein. These data provide evidence for the activation of effector T cells during acute hepatitis E. These responses may play a role in viral clearance from the host in patients with HEV infection.