Objectives: We aimed to investigate the interaction between fasting blood glucose and tumor embolus, and the potential mediation effect of fasting blood glucose on tumor embolus in predicting gastrointestinal tract cancer-specific mortality risk postoperatively. Methods and Results: 4330 patients were consecutively recruited between January 2000 and December 2010, with annual follow-up ending in December 2015. The median follow-up time was 48.6 months. Two optimal cutoff points for fasting blood glucose (6.11 and 11.69 mmol/L) were identified. Patients with fasting blood glucose <6.11 mmol/L and negative tumor embolus had the best survival, and the worst survival was seen in patients with fasting blood glucose >11.69 mmol/L and positive tumor embolus. The risk was highest for patients with fasting blood glucose >11.69 mmol/L and positive tumor embolus (adjusted HR: 11.91, 95% CI: 9.13 to 15.52). Using the Sobel-Goodman mediation test, the proportion of total effect conferred by tumor embolus that was mediated by fasting blood glucose was estimated to be 45.3%. Conclusions: Our findings indicate a synergistic interaction between fasting blood glucose and tumor embolus in predicting the postoperative prognosis of gastrointestinal tract cancer.