Objective To explore the independent risk factors of portal vein thrombosis (PVT) in liver cirrhosis, and to establish and evaluate a risk prediction model for PVT in patients with cirrhosis. Methods A total of 295 cases of cirrhosis hospitalized in Renmin Hospital of Wuhan University from December 2019 to October 2021 were divided into a modeling set (n=207) and an internal validation set (n=88) by the random number table. In addition, patients with cirrhosis hospitalized in Yichang Central People''s Hospital, Wuhan Puren Hospital, No.2 People''s Hospital of Fuyang City and People''s Hospital of China Three Gorges University during the same period were collected as an external validation set (n=92). The modeling set was divided into PVT group (n=56) and non-PVT group (n=151). Univariate analysis was used to preliminarily screen the related indicators of PVT, and then multivariate logistic regression analysis with forward stepwise regression was used to determine independent risk factors for PVT. A nomogram prediction model was constructed based on the independent risk factors obtained. The internal and external validation set were used to verify the predictive ability of the model. Distinction degree was used to evaluate the ability of the model to distinguish patients with or without PVT. Hosmer-Lemeshow goodness-of-fit test was used to evaluate the consistency between predicted risk and the actual risk of the model. Results Univariate analysis showed that smoking, history of splenectomy, trans-jugular intrahepatic portosystemic shunt (TIPS), gastrointestinal bleeding and endoscopic variceal treatment, and levels of hemoglobin, alanine aminotransferase, aspartate aminotransferase and D-dimer were significantly different between the PVT group and the non-PVT group (P<0.05). Multivariate logistic regression analysis found that smoking (P=0.020, OR=31.21, 95%CI: 1.71-569.40), levels of D-dimer (P=0.003, OR=1.12, 95%CI: 1.04-1.20) and hemoglobin (P=0.039, OR=0.99, 95%CI: 0.97-1.00), history of TIPS (P=0.011, OR=18.04, 95%CI: 1.92-169.90) and endoscopic variceal treatment (P=0.001, OR=3.21, 95%CI: 1.59-6.50) were independent risk factors for PVT in patients with liver cirrhosis. Receiver operator characteristic (ROC) curve analysis showed that the area under the ROC curve (AUC) for the internal validation set was 0.802 (95%CI: 0.709-0.895) (P<0.001), and the AUC for the external validation set was 0.811 (95%CI: 0.722-0.900) (P<0.001). Both AUC were larger than 0.75. The calibration curve of Hosmer-Lemeshow goodness-of-fit test showed that the P values of both internal validation set (χ2=3.602, P=0.891) and the external validation set (χ2=11.025, P=0.200) were larger than 0.05. Conclusion Smoking, history of TIPS or endoscopic variceal treatment, levels of D-dimer and hemoglobin are independent risk factors for PVT in patients with liver cirrhosis. The prediction nomogram model based on the above factors has strong predictive ability.