Signal sequence receptor subunit delta (SSR4) gene is reported to encode the translocon-associated protein δ and related with the human immune regulation. However, the expression of SSR4 in colon adenocarcinoma (COAD) and its correlation with clinical treatment remains unclear.SSR4 mRNA expression level and its relationship with tumor infiltrating lymphocytes (TILs) in COAD were evaluated through several databases. Furthermore, the study collected 238 cases of COAD tissue samples to detect the association of SSR4 protein expression level in TILs with clinical pathological information, and the prognosis of COAD.SSR4 mRNA was significantly highly expressed in COAD tissues and significantly correlated with several types of TILs in COAD. Moreover, SSR4 highly expressed in many types of TILs, especially highly expressed in plasma cell from COAD patients with advanced TNM stage. High SSR4 protein expression in TILs was associated with lymph node metastasis, distant metastasis, American Joint Committee on Cancer (AJCC) staging, and Response Evaluation Criteria in Solid Tumors (RECIST) efficacy. COAD patients with high SSR4 expression in TILs had better overall survival.In conclusion, high SSR4 mRNA and protein expression in TILs can be used as a prognostic biomarker for predicting better overall survival and treatment efficacy in COAD patients.