Erosive oral lichen planus (OLP) is a chronic, disabling mucocutaneous dysimmune rare disease characterized by mucosal inflammatory erosive lesions with pathological evidence for a marked CD8+ cytotoxic T-lymphocyte (CTL) infiltration. However, the specificity of lesional CTL in OLP has never been analyzed. To investigate the molecular mechanisms underlying dysregulation of T-cell immune responses in patients with OLP, we studied the diversity and antigen specificity of the TCR expressed by CD8+ T cells using dextramer staining, spectratyping, and TCR sequencing in 10 OLP patients undergoing extracorporeal photochemotherapy. Expansions of TCRVβ3-bearing CD8+ T cells were found in peripheral blood and in lesional tissues of OLP patients. Spectratyping and sequencing studies identified specific clonotypes in each patient. These expansions were enriched with human papillomavirus 16 (HPV16)-specific CD8+ T cells in HLA-A*0201+ patients as shown by their immune recognition of the E711-20 immunodominant epitope. Under treatment with extracorporeal photochemotherapy, clonotypic CD8+ T-cell expansions decreased in parallel with clinical remission. Altogether, these data establish a link between HPV infection and OLP pathogenesis by identifying a massive clonal expansion of CD8+ T cells with increased frequency of HPV 16-specific CD8+ T cells in OLP patients.