Recognition of tumor cells by cytolytic T lymphocytes depends on cell surface MHC class I expression. As a mechanism to evade T cell recognition, many malignant cancer cells, including those of prostate cancer, down-regulate MHC class I. For the majority of human cancers, the molecular mechanism of MHC class I down regulation is unclear, although it is well established that MHC class I down-regulation is often associated with the down-regulation of multiple genes devoted to antigen presentation. Since the promyelocytic leukemia (PML) proto-oncogene controls multiple antigen-presentation genes in some murine cancer cells, we analyzed the expression of proto-oncogene PML and MHC class I in high-grade prostate cancer. We found that 30 of 37 (81%) prostate adenocarcinoma cases with a Gleason grade of 7-8 had more than 50% down-regulation of HLA class I expression. Among these, 22 cases (73.3%) had no detectable PML protein, while 4 cases (13.3%) showed partial PML down-regulation. In contrast, all 7 cases of prostate cancer with high expression of cell surface HLA class I had high levels of PML expression. Concordant down-regulation of HLA and PML was observed in different histological patterns of prostate adenocarcinoma. These results suggest that in high-grade prostate cancer, malfunction of proto-oncogene PML is a major factor in the down-regulation of cell surface HLA class I molecules, the target molecules essential for the direct recognition of cancer cells by cytolytic T lymphocytes.