Aims and Background. Discs large homolog 1 (DLG1) belongs to the modular proteins Membrane Associated Guanylate Kinases (MAGUKs) and plays a major role in the formation of cell-cell junctions and cell polarity. DLG1 varies in expression and localization among malignancies. However, the clinical significance of DLG1 in the context of human colorectal cancer (CRC) remains unclear. The purpose of this study study is to determine the association of DLG1 with clinicopathological characteristics and prognosis of CRC patients. Methods. DLG1 expression in human CRC was detected by immunohistochemical analysis and validated with mRNA data from a high-throughput sequencing TCGA datasets. The association of DLG1 expression with clinicopathological features in CRC patients was then statistically analyzed. Results: Immunohistochemistry analysis found that DLG1 expression was significantly elevated in CRC tissues, compared with the expression in adjacent non-cancerous colon tissues (P=0.000). High DLG1 expression was significantly associated with advanced clinical stage (P=0.011) and enhanced tumor invasion (P=0.002). The TCGA mRNA expression data revealed that DLG1 mRNA expression was up-regulated in CRC tissues with advanced clinical stage (P=0.008), enhanced tumor invasion (P=0.042), lymph node metastasis (P=0.030), and distant metastasis (P=0.043). Kaplan-Meier survival curves revealed that CRC patients with high DLG1 levels had shorter survival (P=0.040). Furthermore, DLG1 was an independent prognostic factor for CRC patients (HR 2.202, 95% CI 1.057-4.587; P=0.035). Conclusions. These findings suggest that the increased expression of DLG1 may be predictive of an unfavorable prognosis in CRC patient and serve as a novel therapeutic target in this malignancy.