Bullous pemphigoid (BP) is a subepidermal autoimmune blistering disease caused by autoantibodies targeting the juxtamembranous extracellular noncollagenous 16A (NC16A) domain of human collagen XVII (also known as BP180). Because T-helper (Th) cells are essential for antibody responses to antigens, we adopted an assay to map the immunodominant Th2-cell epitopes in NC16A. We synthesized 22 overlapping peptides spanning the entire sequence of BP180-NC16A and investigated the reactivity of Th2 cells from patients with BP to these peptides using the Enzyme-Linked ImmunoSpot (ELISPOT) assay. We screened two epitope peptides, P2 (492–506 aa: VRKLKARVDELERIR) and P5 (501–515 aa: ELERIRRSILPYGDS), and confirmed that these epitopes play a dominant role in stimulating CD4⁺ T-cell proliferation and Th2 IL-4 cytokine production, and activating B cells to secrete autoantibodies. These immunodominant epitopes are HLA-DR-restricted and were observed in subjects with different HLA alleles. This work contributes to elucidation of the epitope-mediated immunologic pathogenesis of BP, and the identified Th2-cell epitopes are candidates for epitope-specific therapeutic strategy.