Background and Aims Portal hypertension is characterized by an increased portal pressure gradient (PPG). However, the conventional method for PPG measurement is difficult and risky, so it is challenging to implement in a clinical setting routinely. Previous animal experiments and human tests have shown the feasibility and accuracy of the endoscopic ultrasound-guided portal pressure gradient (EUS-PPG) measurement techniques. A recent prospective study involving patients with subacute portal hypertension caused by occlusion of the small hepatic veins verified the consistency between EUS-PPG and hepatic venous pressure gradient (HVPG). However, there is no report assessing EUS-PPG measurement in patients with cirrhotic portal hypertension in China. Therefore, this study was performed to investigate the accuracy, feasibility, and safety of EUS-PPG measurement in cirrhotic portal hypertension.Methods A total of 52 patients with cirrhotic portal hypertension admitted to the Third Xiangya Hospital of Central South University from March 2022 to August 2022 were enrolled for EUS-PPG measurement. The EUS-PPG measurement results and their associations with the clinical features of patients were analyzed.Results In the 52 patients, 47 cases had a previous or recent history of esophageal and gastric variceal bleeding (14 cases had previous devascularization and splenectomy). EUS-PPG was successfully performed in 51 cases (98%), and technical failure occurred in one case. The approaches for portal vein puncture included that through the gastric wall (42 cases) or the duodenum (9 cases) and punch of the hepatic vein (10 cases) or retrohepatic inferior vena cava (41 cases) through the gastric wall. The operative time was (15.5±3.4) min. Of the 51 patients, the average portal vein pressure was (21.0±7.1) mmHg, the hepatic vein pressure was (5.7±5.5) mmHg and the PPG was (15.3±4.9) mmHg. Five patients underwent simultaneous portal vein and left gastric vein puncture for pressure measurement, and the results showed that the two pressure values were highly correlated (r=0.99, P=0.000 66). No adverse events were observed in all patients. The PPG value in patients who had previously undergone devascularization and splenectomy was significantly lower than that in those who had not undergone this procedure (12.8 mmHg vs. 16.3 mmHg, P<0.05), the PPG value in patients with a history of esophageal and gastric variceal bleeding was significantly higher than that in those with no history of this complication (16.8 mmHg vs. 11.8 mmHg, P<0.05), and there was no significant difference in PPG value among patients with different Child-Pugh classifications (P>0.05).Conclusion EUS-PPG is a new method for directly determining the pressure difference between the portal vein and hepatic vein, which is accurate, reliable, safe, and feasible. Transduodenal portal vein puncture or puncture of the dilated main branches of the portal vein can be performed instead when technical difficulties occur during conventional portal vein puncture.