ObjectiveTo explore the expression and clinical significance of plasma soluble podoplanin (sPDPN) in patients with colorectal cancer (CRC). MethodsTCGA-READ, TCGA-COAD datasets were obtained to compare expression level of PDPN mRNA in CRC tissues and adjacent tissues, and to explore the relationship between expression of PDPN mRNA and the prognosis of CRC patients. A total of 85 CRC patients (CRC group) underwent surgery in the Second Affiliated Hospital of Xuzhou Medical University from November 2020 to December 2022, and 100 healthy volunteers from the hospital were collected as a control group to detect the expression levels of plasma sPDPN of the two groups, and exploring the relationship between sPDPN expression and the clinicopathological characteristics of the CRC patients. The ROC curves of sPNPD, sugar antigen 199 (CA199) and carcinoembryonic antigen (CEA) were drawn simultaneously, and the predictive value of sPDPN for CRC was explored by logistic regression model. ResultsThe results of TCGA dataset showed that expression level of PDPN mRNA was upregulated in CRC tissues compared with adjacent tissues/paired adjacent tissues (P<0.05), and patients with high expression level of PDPN mRNA had better prognosis than low expression patients (P=0.045). The expression level of sPDPN was (3.50±1.77) ng/mL in CRC group, which was higher than (1.95±0.46) ng/mL of the control group (P<0.01). The expression level of sPDPN was higher in CRC patients at Ⅲ+Ⅳ clinical stage (P=0.026) and N1–2 stage (P=0.049). Compared with CA199 and CEA, sPDPN had the highest area uncer curve value of 0.882 (0.832, 0.932), and was an risk predictor of CRC [OR=14.769, 95%CI (5.867, 37.174), P<0.001]. ConclusionThe sPDPN is highly expressed in the plasma of CRC patients and has a certain clinical utility for diagnosis of CRC, and evaluation of clinical staging and lymph node metastasis.