Background: CD47 belongs to the immunoglobulin superfamily and is overexpressed in many tumor types. CD47 plays an important role in suppressing phagocytosis through binding to transmembrane protein SIRP-alpha on macrophages. Targeting CD47 is a novel strategy for cancer immunotherapy and is being evaluated in ongoing clinical trials. However, molecular characteristics of CD47-overexpressed colorectal cancer (CRC) are largely unknown. Methods: We retrospectively reviewed CRC patient samples (n = 14786) submitted to a commercial CLIA-certified laboratory (Caris Life Sciences, Phoenix AZ). Next-generation sequencing of DNA and RNA (whole-transcriptome sequencing) and immunohistochemistry were performed. Correlation of CD47 expression with danger-associated molecular pattern (DAMP)-related genes (HMGB1, CALR, ANXA1, HSP90AA1, HSPA1A, and CXCL10) expressions was tested. DAMP signature calculated as composite z-score of the DAMP related genes was compared between CD47-high and -low patients classified according to the median level of CD47 expression. Distributions of KRAS and BRAF mutations, consensus molecular subtype (CMS), and signatures of oncogenic signaling pathways were compared between CD47-high and -low patients. In addition, overall survival (OS) was compared between CD47-high and -low patients available for survival data. Results:CD47 expression level was significantly higher in metastatic compared to primary lesions (1.07-fold, q < 0.05) and microsatellite instability high tumors compared to microsatellite stable tumors (1.15-fold, q < 0.05). CD47 expression was positively correlated with DAMP genes expression except for HSPA1A, and the DAMP signature (median score [MS]: 2.66 vs -2.29, q < 0.05) was significantly increased in CD47-high patients. KRAS mutations were less prevalent (45.87% vs 50.05%) and CMS1(17.72% vs 14.42%) and CMS4 (40.33% vs 27.28%) were more prevalent in CD47-high patients, while no difference was observed in the prevalence of BRAF mutations between CD47-high and -low patients. Signatures of EMT (MS:2.91 vs -3.19), TGF-beta (MS:3.72 vs -3.52), angiogenesis (MS:2.95 vs -2.78), MAPK (MS:4.99 vs -4.12), PI3K (MS:2.41 vs -2.03), and immune-related signaling pathways (MS:1.20 vs -2.51) were significantly enriched in CD47-high patients (all q < 0.05). CD47-high patients (n = 4873) showed significantly worse OS than CD47-low patients (n = 4898) (median OS, 32.4 vs 37.6 months; hazard ratio = 1.158, p< 0.01). Conclusions: Highly CD47-expressed CRC harbored activation of DAMPs and oncogenic signaling pathways that linked to aberrant tumor microenvironment and worse prognosis. Our results support intensive treatment strategies using CD47 inhibitors combined with cytotoxic agents and molecular targeted agents (such as anti-VEGF agents) in CD47-overexpressed CRC.