Abstract: Objective To investigate the clinical value of plasma soluble podoplanin (sPDPN) as a novel biomarker for assessing the risk, early diagnosis, and therapeutic monitoring of venous thromboembolism (VTE) associated with gastrointestinal tumors. Methods A total of 102 patients who were initially diagnosed with gastrointestinal tumors at the Second Affiliated Hospital of Xuzhou Medical University from November 2020 to December 2021 were enrolled. Meanwhile, 100 healthy volunteers undergoing routine physical examinations were included as controls. The levels of plasma sPDPN before and after surgery were measured by enzyme-linked immunosorbent assay (ELISA) using mouse anti-human PDPN monoclonal antibodies SZ163 and SZ168. Postoperative VTE risk was evaluated using the Caprini risk assessment model. Results Preoperative sPDPN levels in patients with gastrointestinal tumors were significantly higher than those in the control group (P<0.01). On postoperative day 7, sPDPN levels decreased and showed no significant difference compared with those in the control group (P>0.05). The combination of sPDPN and the Caprini score demonstrated a higher diagnostic value for VTE risk (AUC=0.929, sensitivity=85.90%, specificity=94.61%) than either indicator alone. Conclusions sPDPN may serve as a novel plasma biomarker for tumor-associated VTE and holds potential clinical value in VTE risk assessment, early diagnosis, and therapeutic monitoring among patients with gastrointestinal tumors.