Desquamative gingivitis (DG) denotes a heterogeneous immune-mediated disease for which early diagnosis represents a great challenge. The main aim of this study is to validate diagnostic concordance between specific Optical Coherence Tomography (OTC) patterns for DG related to oral Lichen Planus (OLP), Pemphigus Vulgaris (PV), and Mucous Membrane Pemphigoid (MMP) and definitive histological diagnosis. Forty-three patients with suspected immune-mediated DGs, were progressively recruited. Before biopsy, an OCT preliminary evaluation was performed using specific pre-determined OCT diagnostic patterns (i.e., morphology and localization of blisters, status of the basal membrane, epithelial thickness, presence/absence of acantholytic cells into blister and/or inflammatory infiltrate) related to OLP, PV and MMP. After histological confirmation, OCT and histological diagnoses were compared. Using pre-determined patterns, OCT diagnoses of DGs were: 22 (51%) OLP, of which 11 (26%) were with the bullous variant, 4 (9%) PV and 6 (14%) MMP. The same diagnoses were found by histological investigations (with the main OCT discriminatory potential for the bullous variant of OLP). The concordance between the two diagnostic methods was confirmed by the Fisher exact test (p-value < 0.01). These specific OCT patterns show a diagnostic reliability in 100% of the cases investigated, suggesting their accuracy to support the complex diagnosis and management of immune-mediated DGs.