Background Noninvasive methods have been established to detect clinically significant portal hypertension in liver cirrhosis with variable limitations. The von Willebrand factor (vEF) has been found to increase in liver cirrhosis. Aim The aim of this study was to explore the vEF and VITRO (von Willebrand factor antigen/platelet ratio) score in the prediction of variceal bleeding in patients with portal hypertension. Materials and methods Fifty patients with hepatitis C-related liver cirrhosis (25 patients with variceal bleeding and 25 without variceal bleeding) as well as 80 healthy controls were included. Laboratory investigations and upper gastrointestinal endoscopy were performed in all patients. Serum vEF was measured in the patient and the control group. The VITRO score was calculated. Results The mean levels of the vEF antigen and the VITRO score were higher in patients with variceal bleeding compared with patients without variceal bleeding and controls (P<0.001). At levels of at least 100.1 ng/ml and at least 0.732, the vEF and the VITRO score could predict variceal bleeding with a sensitivity and a specificity of 92 and 99.9% for the vEF and 80 and 68% for the VITRO score (area under the curve=0.982 and 0.843), respectively. Levels of vEF were correlated positively with esophageal varices grade. Conclusion Serum vEF level and the VITRO score are potential noninvasive biomarkers for the prediction and risk stratification of variceal bleeding in hepatitis C-related liver cirrhosis.