HLA class I antigen defects are frequently found in malignant cells. They appear to play a role in the clinical course of the disease, probably because they provide tumor cells with a mechanism to escape cytotoxic T lymphocyte (CTL) recognition and destruction. Expression of HLA class I antigens, however, is not always associated with the susceptibility of tumor cells to CTL lysis. Many mechanisms may underlie this finding, including the lack of tumor antigen (TA)-derived peptide presentation by a given HLA class I allospecificity, and/or the expression of immunosuppressive molecules such as HLA-G. These findings emphasize the need to develop probes to measure HLA class I allospecificity-TA peptide complex expression in malignant cells. Furthermore, the evaluation of the role of HLA class I antigens in the interaction of malignant cells with host immune cells should take into account the potential interference of tumor-derived immunomodulators.