Programmed death ligand 1 (PD-L1) is an immune-checkpoint regulator. Expression of PD-L1 in a subset of head and neck squamous cell carcinoma (HNSCC) was linked to improved response to immunotherapy. Oral potentially malignant disorders (OPMDs) are characterized by increased risk for malignant transformation. We investigated the expression of PD-L1 in immune cells (ICs) and epithelial cells of OPMD, which is essential to prevent progression to malignancy. Immunohistochemistry analyses in HNSCC whole excision tissue sections (104 patients) indeed demonstrated predominant expression of PD-L1 in the epithelial margins (~86%). This directly correlated with PD-L1 expression in underlying ICs (P=0.0172) with a predominating lichenoid pattern of IC infiltrate. Immunoblotting analyses demonstrated the role of human recombinant IFN-γ in the upregulation of PD-L1 expression in the oral premalignant cell line (DOK) with implications of downstream activation of pS6. Our work suggests a role for IFN-γ/PD-L1 in the immune escape of OPMDs.