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The assessment of programmed death-ligand 1 (PD-L1) combined positive scoring (CPS) in head and neck squamous cell carcinoma (HNSCC) is challenged by pre-analytical and inter-observer variabilities. An educational program to compare the diagnostic performances between local pathologists and a board of pathologists on 11 challenging cases from different Italian pathology centers stained with PD-L1 immunohistochemistry on a digital pathology platform is reported. A laboratory-developed test (LDT) using both 22C3 (Dako) and SP263 (Ventana) clones on Dako or Ventana platforms was compared with the companion diagnostic (CDx) Dako 22C3 pharm Dx assay. A computational approach was performed to assess possible correlations between stain features and pathologists' visual assessments. Technical discordances were noted in five cases (LDT vs. CDx, 45%), due to an abnormal nuclear/cytoplasmic diaminobenzidine (DAB) stain in LDT (n = 2, 18%) and due to variation in terms of intensity, dirty background, and DAB droplets (n = 3, 27%). Interpretative discordances were noted in six cases (LDT vs. CDx, 54%). CPS remained unchanged, increased, or decreased from LDT to CDx in three (27%) cases, two (18%) cases, and one (9%) case, respectively, around relevant cutoffs (1 and 20, k = 0.63). Differences noted in DAB intensity/distribution using computational pathology partly explained the LDT vs. CDx differences in two cases (18%). Digital pathology may help in PD-L1 scoring, serving as a second opinion consultation platform in challenging cases. Computational and artificial intelligence tools will improve clinical decision-making and patient outcomes.