Using a set of 11 synthetic peptides containing regions of the polypeptide encoded by open reading frame 2 (ORF2) of the hepatitis E virus (HEV) genomic RNA, two immunodominant regions were found. One region is located at position 546-580 amino acids (aa). Another very strong immunodominant region was identified at position 394-470 aa. Five peptides spanning this region were found to have antigenic reactivity. One of these 5 peptides demonstrated specific reactivity with 81% of sera obtained from HEV-infected patients. To elucidate the antigenic structure of this region in fine detail, an additional set of 35 overlapped 20-mer peptides spanning the region 388-493 aa was synthesized. Two subregions with very strong antigenic reactivity, one located around position 420-440 aa and another around 450-460 aa, were identified. Thus, in addition to the strong epitope(s) in the C-terminal region of the ORF2 protein previously identified, at least two immunodominant regions were found at positions 394-470 and 546-580 aa.