Simple SummaryAmongst colorectal cancers, there is significant heterogeneity, which hinders the search for a single disease detection approach. Clinical prognostic markers are urgently needed. The aim of our prospective study was to analyse the possible role of pre-operative soluble SIGLEC5 plasma levels in patient prognosis and evolution. In a cohort of 114 patients with colorectal cancer, our data confirmed the relevance of soluble SIGLEC5 levels as a prognosis marker and exitus predictor. Altogether, our data indicate that levels of this protein could be a novel and promising biomarker for patients with colorectal cancer.Colorectal cancer (CRC) is the second most deadly and third most commonly diagnosed cancer worldwide. There is significant heterogeneity among patients with CRC, which hinders the search for a standard approach for the detection of this disease. Therefore, the identification of robust prognostic markers for patients with CRC represents an urgent clinical need. In search of such biomarkers, a total of 114 patients with colorectal cancer and 67 healthy participants were studied. Soluble SIGLEC5 (sSIGLEC5) levels were higher in plasma from patients with CRC compared with healthy volunteers. Additionally, sSIGLEC5 levels were higher in exitus than in survivors, and the receiver operating characteristic curve analysis revealed sSIGLEC5 to be an exitus predictor (area under the curve 0.853; cut-off > 412.6 ng/mL) in these patients. A Kaplan–Meier analysis showed that patients with high levels of sSIGLEC5 had significantly shorter overall survival (hazard ratio 15.68; 95% CI 4.571–53.81; p ≤ 0.0001) than those with lower sSIGLEC5 levels. Our study suggests that sSIGLEC5 is a soluble prognosis marker and exitus predictor in CRC.