Simple Summary Cancer treatments often have side effects that may impair patients' quality of life. Our research aimed to create a predictive tool able to foresee the likelihood of these severe complications. We used medical data from 267 gastrointestinal cancer patients, applied a particular type of computer model known as a Bayesian network, and evaluated its predictions against real outcomes. The model accurately predicted the risk of developing severe haematological toxicity in 80-85% of cases. This tool, if further validated and refined, may help to identify a vulnerable subset of patients who might benefit from personalized treatment plans.Abstract Purpose: Severe toxicity is reported in about 30% of gastrointestinal cancer patients receiving 5-Fluorouracil (5-FU)-based chemotherapy. To date, limited tools exist to identify at risk patients in this setting. The objective of this study was to address this need by designing a predictive model using a Bayesian network, a probabilistic graphical model offering robust, explainable predictions. Methods: We utilized a dataset of 267 gastrointestinal cancer patients, conducting preprocessing, and splitting it into TRAIN and TEST sets (80%:20% ratio). The RandomForest algorithm assessed variable importance based on MeanDecreaseGini coefficient. The bnlearn R library helped design a Bayesian network model using a 10-fold cross-validation on the TRAIN set and the aic-cg method for network structure optimization. The model's performance was gauged based on accuracy, sensitivity, and specificity, using cross-validation on the TRAIN set and independent validation on the TEST set. Results: The model demonstrated satisfactory performance with an average accuracy of 0.85 (& PLUSMN;0.05) and 0.80 on TRAIN and TEST datasets, respectively. The sensitivity and specificity were 0.82 (& PLUSMN;0.14) and 0.87 (& PLUSMN;0.07) for the TRAIN dataset, and 0.71 and 0.83 for the TEST dataset, respectively. A user-friendly tool was developed for clinical implementation. Conclusions: Despite several limitations, our Bayesian network model demonstrated a high level of accuracy in predicting the risk of developing severe haematological toxicity in gastrointestinal cancer patients receiving 5-FU-based chemotherapy. Future research should aim at model validation in larger cohorts of patients and different clinical settings.