HLA-G as a non-classical MHC class I molecule exhibits a limited tissue distribution and exerts multiple immune regulatory functions including the induction of immune tolerance. In addition, HLA-G has been detected in some tumors of different histology and therefore may represent a novel immune escape mechanism of tumor cells. Despite the immunogenicity of renal cell carcinoma (RCC), outgrowth of tumor cells occurs which might be attributable to abrogation of efficient anti-tumor responses. We here review the potential role of HLA-G in RCC immunology, the HLA-G expression pattern and its functional consequences on immune responses. A heterogenous constitutive and interferon-gamma inducible HLA-G mRNA and protein expression was found in RCC cell lines and tumor lesions, but not in autologous normal kidney epithelium. HLA-G transcription and protein expression was detected at a high frequency in primary RCC lesions and RCC cell lines. Functional studies performed with alloreactive natural and lymphokine activated killer cells as well as antigen-specific CD8+ T cell populations demonstrated that HLA-G expression inhibits lysis of RCC cells by these different immune effector cells, whereas HLA-G- normal kidney cells were recognized. Thus, aberrant HLA-G expression might participate in evasion of these tumor cells from immunosurveillance.