We have investigated the role of antigen-processing machinery (APM) component defects in HLA class I antigen down-regulation in laryngeal squamous cell carcinoma (SCC) lesions and assessed the clinical significance of these defects. To this end, 63 formalin-fixed, paraffin-embedded tumor lesions were examined for APM component and HLA class I antigen expression by immunohistochemistry. Calnexin, calreticulin, and ERp57 were down-regulated in ∼25% of the lesions tested, whereas LMP2, TAP1, tapasin, and HLA class I antigens were down-regulated in at least 70% of the lesions tested. LMP2 and tapasin expression was significantly correlated with HLA class I antigen expression suggesting APM component defects as a mechanism underlying HLA class I antigen down-regulation in laryngeal SCC lesions. The expression of most APM components and HLA class I antigens was correlated with the extent of CD8⁺ T cell infiltration into tumor lesions. Furthermore, LMP2 and HLA class I antigen down-regulation and low CD8⁺ T cell infiltration were significantly associated with reduced patients' survival. Multivariate analysis identified HLA class I antigen down-regulation as an independent unfavorable prognostic marker. This association is likely to reflect the reduction in the extent of CD8⁺ T cell infiltration in laryngeal SCC lesions. (Cancer Res 2006; 66(18): 9281-9)