Aberrant expression of human leukocyte antigen G (HLA-G) has been proposed to be involved in tumor escape mechanisms. It has been also proposed that detection of HLA-G might service as a potential biomarker for diagnosis or prediction of the clinical outcomes in ovarian and breast cancers, carcinoma of the lung and endometrial cancer. The aim of this current study is to determine if HLA-G is expressed in colorectal carcinomas and if the expression is associated with clinicopathological and prognostic data. The expression of HLA-G was investigated immunohistochemically in 201 patients with colorectal carcinomas. The correlation between HLA-G status, clinicopathological factors and the overall survival rate was analyzed. In this prospectively study, HLA-G protein expression was observed in 64.6% (130/201) of the primary site colorectal carcinomas, but not in the normal colorectal tissues or benign adenomas. HLA-G expression in the tumors was significantly correlated with the depth of invasion, histological grade, host immune response, lymph nodal metastasis and clinical stages of the disease (P=0.001, 0.0001, 0.002, 0.001 and 0.031, respectively). Patients with HLA-G positive tumors had a significantly shorter survival time than those patients with tumors that were HLA-G negative (P=0.0001). As well, in multivariate analysis, HLA-G demonstrated an independent prognostic factor (P=0.021, relative risk 3.14; 95% confidence interval, 1.34-8.10). Therefore, it can be gathered that HLA-G might serve as an independent prognostic factor for colorectal cancer patients.