Objective     To explore the role of versican (VCAN) in ESCC prognosis based on bioinformatics data. Methods    First, three RNA microarray datasets of ESCC were downloaded from GEO database, which were then integrated and used to explore differentially expressed genes (DEGs). The subsequent analysis was conducted based on the results of these DEGs: (1) The STRING database was used to construct a protein-protein interaction (PPI) network;(2) molecular complex detection software was used to analyze the modules of the PPI network, of which the most significant modules were chosen, and hub genes were the genes included in the chosen modules; (3) high-throughput RNA sequencing data from TCGA and GTEx databases were used to verify the expression of these hub genes to confirm whether they were differentially expressed; (4) the survival curve analysis of confirmed DEGs was conducted to select genes that had significant influence on the survival of ESCC; (5) TIMER database was used to analyze the relationship between the gene expression of VCAN and the abundance of tumor-infiltrating immune cells (TIICs) and gene markers in these cells; (6) Targetscan and miRDB software were used to predict the miRNAs that could regulate VCAN, and Cytoscape software was used to construct the regulatory network. Results    A total of 630 DEGs and 32 hub genes were found, of which VCAN was an up-regulated DEG, and high expression of VCAN was significantly associated with poor prognosis of ESCC. Moreover, VCAN could also play a role in the immune microenvironment of ESCC, which was mainly manifested by a significant positive correlation between the abundance of VCAN and the abundance of M2 macrophages gene markers, some of which had been reported to be associated with poor prognosis of ESCC. Finally, we also found that VCAN could be regulated by 15 miRNAs in ESCC, some of which had been reported to be associated with ESCC prognosis. Conclusion    This study provides direct and indirect comprehensive evidence for the role of VCAN in ESCC prognosis. The direct evidence is that the survival curve shows that highly expressed VCAN is significantly associated with the poor prognosis of ESCC, and the indirect evidence is that VCAN is positively related to some markers which indicate poor prognosis in the ESCC immune microenvironment, and VCAN can be regulated by some prognostic miRNAs in ESCC.