Background: Several studies give a superficial description that HEPACAM family member 2 (HEPACAM2) seems to be a prognostic biomarker in colon adenocarcinoma (COAD). While, systematic and in-depth research about diagnostic and prognostic value of HEPACAM2 in COAD patients is lacked. Besides, relationship between HEPACAM2 gene expression levels and immune cell infiltration is unclear. Methods: Firstly, we analyzed the differential expression levels of HEPACAM2 gene and diagnostic value from different databases. Secondly, a cohort of Guangxi COAD patients was established to verify HEPACAM2 expression pattern and diagnostic value. Thirdly, univariate and multivariate survival analysis of the prognostic value of HEPACAM2 gene in patients with COAD was performed. We also utilized joint-effects analysis and comprehensive prognosis analysis to investigate the prognostic value of HEPACAM2 and related genes. Finally, we explored the relationship between HEPACAM2 gene expression levels and immune cell infiltration.Results: In several biological databases, HEPACAM2 mRNA expression level in COAD tumor tissues was significantly lower than that of adjacent normal tissues. The diagnostic ROC curve results indicated that HEPACAM2 gene had a high diagnostic value in COAD. The qPCR verification results in the Guangxi cohort showed that HEPACAM2 expression level in COAD tumor tissues was significantly lower than that of adjacent normal tissues (P<0.001), and the diagnostic value was high in COAD (AUC=0.892). The prognostic value analysis showed that low expression of HEPACAM2 gene had a poorer overall survival (OS) in COAD patients when compared with those with high expression ((P = 0.038, HR (95% CI) = 0.635(0.414-0.976)). Joint-effects analysis and comprehensive prognosis analysis showed that high expression of HEPACAM2 combined with high expression of CLCA1, high expression of REP15, and high expression of B3GNT6 were associated with a better overall survival of COAD.Conclusion: This study suggested that the HEPACAM2 may be a diagnostic and prognostic biomarker for COAD. Besides, HEPACAM2 was involved with immune response progress, Chemokine signaling pathway, Ras signaling pathway and Hematopoietic cell lineage.