Background and Aims With the advancement of surgical techniques and clinicians' continuous refinement of surgical approaches, the surgical mortality of pancreaticoduodenectomy (PD) has significantly decreased. However, the incidence of postoperative complications remains high, with postoperative pancreatic fistula (POPF) being the most common and severe. Therefore, this study was conducted to investigate the risk factors for clinically relevant POPF (CR-POPF) after PD and develop a risk prediction model.Methods The clinical data of 365 patients who underwent PD in the Department of Hepatobiliary Surgery of General Hospital of Ningxia Medical University from January 2015 to July 2021 were retrospectively collected. Patients were randomly divided into modeling and validation groups at a ratio of 7∶3 based on a random number generator. Univariate and multivariate Logistic regression analyses were conducted on the modeling group to determine independent risk factors for CR-POPF. A clinical prediction model was constructed and visualized using a nomogram. The discriminative ability was evaluated using the ROC curve, and Bootstrap drew the calibration curve and repeated the self-sampling method for internal validation. The validation group was incorporated into the model to verify the predictive performance of the model by drawing the ROC curve and calibration curve.Results Univariate analysis showed that sex, BMI, history of abdominal surgery, main pancreatic duct diameter, pancreatic texture, neutrophil count, monocyte count, lymphocyte count, the ratio of monocytes to lymphocytes, and postoperative lactate were significantly associated with CR-POPF (all P<0.05). Multivariate Logistic regression analysis revealed that male sex (OR=2.896, 95% CI=1.368-6.390), high postoperative lactate (OR=3.593, 95% CI=2.211-6.172), main pancreatic duct diameter ≤3 mm (OR=0.243, 95% CI=0.102-0.552), and soft pancreatic texture (OR=0.146, 95% CI=0.061-0.331) were independent risk factors for CR-POPF (all P<0.05). A mathematical model was established based on regression coefficients, and a nomogram was constructed for visualization. The area under the ROC curve (AUC) of the model was 0.897 (95% CI=0.857-0.936); calibration assessment showed that the trend of the simulated curve was consistent with the actual curve (MAE=0.014). The validation group data were applied to the prediction model, and the ROC curve for predicting the risk of POPF CR-POPF in the validation group showed an AUC of 0.901 (95% CI=0.844-0.959); the calibration curve demonstrated that the trend of the simulated curve in the validation group was consistent with the actual curve (MAE=0.019).Conclusion Male sex, soft pancreatic texture, main pancreatic duct diameter ≤3 mm, and high postoperative lactate are closely associated with the occurrence of POPF after PD. A predictive model for early postoperative CR-POPF based on these four variables demonstrates good performance and can guide clinicians in making treatment plans for patients undergoing PD.