The potential role of immunological events in the pathogenesis and clinical course of head and neck squamous cell carcinoma (SCCHN) has stimulated interest in the characterization of HLA class I antigen expression in SCCHN lesions, because these molecules play an important role in the interaction of malignant cells with the host's immune system. Therefore in this paper, following a description of the methodology used to analyze HLA class I antigen expression in normal tissues and in malignant lesions, we have reviewed data about the frequency of HLA class I antigen defects in about 500 primary and in about 25 metastatic SCCHN lesions. The mean frequency of total HLA class I antigen loss in primary and metastatic lesions is approx 15% and 40%, respectively. The mean frequency of selective HLA class I antigen loss in primary lesions is approx 37%. This type of abnormality has not been investigated in metastatic lesions so far. The molecular mechanisms underlying HLA class I antigen defects in SCCHN cells have been investigated to a limited extent. The available information suggests that structural defects in beta2m genes are rare. In contrast, functional abnormalities of the antigen processing machinery (APM) components are frequent in SCCHN cells. The latter abnormalities are likely to account for the unusual finding that most of SCCHN cell lines are resistant in vitro to HLA class I antigen restricted, tumor antigen (TA)-specific CTL recognition under basal conditions in spite of the expression of TA and HLA class I antigens. CTL recognition of SCCHN cells is restored by incubation with IFN-gamma. These in vitro findings provide a mechanism for the association between APM component defects in SCCHN lesions and clinical course of the disease and imply that T cell-based immunotherapy of SCCHN may benefit from the intralesional administration of IFN-gamma.