•Esophageal cancer-related gene (ECRG) family has recently been characterized as an integrator and indispensable node in carcinogenesis.•Identification of this issue may be important to guide clinical management of liver cancer in the future.•Consequently, our present data using in silico data-mining analyses as well as immunohistochemistry provide an in-depth insight into the prognostic significance of ECRG family members in liver cancer.•We conclude that ECRG factors may act as an essential role in the progression of liver cancer. Hepatocellular carcinoma (HCC) is a lethal cancer with increasing incidence, yet the molecular biomarkers that have strong prognostic impact and also hold great therapeutic promise remain elusive. Data mining approaches with a set of publicly accessible databases and immunohistochemistry were used to provide a novel insight into the expression pattern and prognostic significance of the esophageal cancer-related gene (ECRG) family members in HCC. We found that elevated mRNA expression levels of ECRG factors were correlated with better overall survival, relapse-free survival and progression-free survival rates in patients with HCC. Subgroup analyses showed significant associations between ECRG expression and survival outcome in select HCC patients. In addition, immunohistochemical and multivariate analysis confirmed increased ECRG4 expression as an independent prognostic indicator for survival. Our data suggest that ECRG factors have significant impacts on the survival of HCC patients. The expression of ECRG factors may be involved in HCC progression and could serve as novel biomarkers for predicting more accurate prognosis.