In a previous study, we demonstrated that human leucocyte antigen G (HLA-G) was aberrantly expressed in a majority of primary colorectal carcinomas, and that the detection of HLA-G expression had a strong and independent prognostic value in human colorectal cancer. In the current study, we look into whether the aberrant expression of HLA-G is also related to non-small cell lung cancer (NSCLC). The expression of HLA-G was investigated immunohistochemically in 106 patients with NSCLC. The correlation between HLA-G status and various clinicopathological parameters was analysed. As well, the level of HLA-G expression was also compared to the survival rate of patients with NSCLC. In total, we found that in 75% (79/106) of the primary site of NSCLC, an aberrant HLA-G expression was detected. However, this expression was not observed in the normal lung tissues. HLA-G expression in NSCLC was significantly correlated with lymph nodal metastasis, clinical stages of the disease, and host immune response (P = 0.0001, 0.0001, and 0.027, respectively). Patients with HLA-G positive tumours had a significantly shorter survival time than those with tumours that were HLA-G negative (P = 0.001). In addition, through multivariate analysis, HLA-G exhibited an independent prognostic factor (P = 0.01, relative risk 4.09; 95% confidence interval 1.40-11.9). All in all, our results indicate that the expression of HLA-G is a characteristic feature of NSCLC, and they suggest that immunostaining by anti-HLA-G antibodies may be a potentially useful prognostic indicator.