Purpose: Human leukocyte antigen-G (HLA-G) is a tumor-associated immunosuppressive molecule involved in tumor escape mechanisms. The aimof this study is to elucidate its prognostic significance in hepatocellular carcinoma (HCC). Experimental Design: Immunohistochemical staining of HLA-G expression as well as tumor infiltrating FoxP3+ regulatory( Tregs) and CD8 + cytotoxic T cells was carried out on tissue microarrays containing 173 HCC tissue specimens. Membrane-bound HLA-G1 protein expression in five human HCC cell lines was detected by Western blot. Results: HLA-G expression was associated with HCC prognosis, especially in early-stage diseases, with high expression independentlya ssociated with shortened overall survival (P = 0.041) and increased tumor recurrence (P = 0.023). HLA-G level was positivelyr elated to Tregs/CD8+ ratio and their combination served as a better prognosticator, patients having concurrent high levels of both variables at more than three times of risk of death and tumor relapse than those with concurrent lowlevels (both P < 0.001). In addition, HLA-G1 expression increased in a concordant manner with the increase of metastatic potential in human HCC cell lines. Conclusions: Overexpression of HLA-G protein in HCC was an independent indicator for poor outcome especially in early-stage disease. The combination of HLA-G expression and Tregs/CD8+ ratio added the prognostic power to both variables, offering a possible strategy of tumor-stroma interaction-oriented cancer immunotherapy. © 2009 American Association for Cancer Research.