HLA class I and II antigen expression in routinely processed head and neck squamous cell carcinoma (HNSCC) primary lesions was evaluated. Paraffin embedded samples from 66 squamous cell carcinomas and 7 verrucous carcinomas were studied immunohistochemically using recently developed anti-HLA class I monoclonal antibodies (MAbs) HC10 and HCA2, and anti-HLA-DR rabbit serum. Percent stained tumor cells were scored in 1 of 5 categories. The scores of 40 tumors were compared to the staining results obtained on frozen sections of the corresponding lesions, including those of the anti-class I MAb W6/32. High percentage-matched scores for paraffin and frozen sections were obtained, with HC10 vs. HC10, HC10 vs. W6/32, and anti-HLA-DR vs. anti-HLA-DR showing the best correlations. In the squamous cell carcinomas HLA class I expression was high (i.e., in 49/66 lesions more than 50% cells were stained), and correlated with the degree of differentiation, and inversely with the modified Jakobsson score. HLA class II expression (more than 5% cells stained) was found in 21/66 tumors and correlated inversely with the degree of differentiation. All verrucous carcinomas exhibited very high HLA class I expression, whereas class II was locally expressed in 5/7 lesions. Comparison of 4 subsites of HNSCC showed that carcinomas of the oral cavity had the highest HLA class I expression. This suggests susceptibility to CD8+ T cells, and together with the well developed submucosal lymphoid tissue, makes the oral cavity carcinomas probably well suited for local immunotherapeutic approaches in HNSCC.