Background: Human leukocyte antigen (HLA)-G is a nonclassical HLA class I molecule with modulatory effects on NK and T cells. Because HLA-G expression is frequently detected in different solid tumors, it may be involved in tumor immune evasion. Objective: This study was designed to elucidate the prognostic value of HLA-G in hepatocellular carcinoma (HCC) and pancreatic adenocarcinoma (PADC). The influence of hepatitis B virus (HBV) infection on HLA-G expression was also evaluated in patients with HCC. Methods: HLA-G expression was investigated in tumor tissues from patients with HCC (n=74) or PADC (n=42) with immunohistochemical techniques. The presence of HBV genome was also examined in HCC tumor tissues by PCR. Results: HLA-G expression was detected in 66% of PADC and in 31% of HCC samples. In contrast to HCC, HLA-G overexpression was associated with advanced stages and grades in PADC. HBV genome was detected in 31% of HCC samples but we found no correlation between HLA-G expression and the presence of HBV genome in these tumors. Conclusion: Our findings showed that HLA-G overexpression in tumor tissue correlated with poor prognosis in PADC. HLA-G expression is apparently affected by the patient’s genetic background and other epigenetic factors rather than by HBV infection.