Renal epithelial cancers represent a heterogeneous group of neoplasms arising from the malignant transformation of presumed diverse cell lineages. We recently demonstrated that tumor-specific up-regulation of human leukocyte antigen (HLA)-G, a nonclassical HLA class Ib molecule that might be involved in immune evasion by tumor cells, frequently occurs in conventional (clear cell) renal carcinoma. We here examined whether HLA-G activation is a common process affecting all types of renal epithelial tumors. We analyzed a series of 38 paraffin-embedded tumors including clear cell, papillary, chromophobe, collecting duct carcinoma, and oncocytoma. Seven of 12 (58%) clear cell tumors were positive by immunohistochemistry, whereas all of the other subtypes of renal carcinoma were negative for HLA-G expression. Developing or adult normal renal tissue were devoid of HLA-G expression. We also observed that ectopic expression of HLA class II antigens occurs more frequently in clear cell renal carcinoma than in other subtypes of renal tumors. Moreover, in contrast to the common observation of a down-regulation of major histocompatibility complex class Ia antigens reported in various tumors, the concomitant study of the same biopsies for classical HLA class Ia antigen expression revealed a general increase of HLA class Ia expression, regardless of histological subtypes. These results provide evidence for the heterogeneity of major histocompatibility complex expression patterns in renal carcinoma and support the hypothesis that specific mechanisms underlying the malignant transformation into clear cell renal carcinoma up-regulate expression of HLA-G and to a lesser extent HLA class II molecule expression. Considering the immunotolerant role of HLA-G toward the immune response, these mechanisms may thus provide renal cell carcinoma tumor cells with additional means to escape immune surveillance.