Background and Aims Acute lower extremity deep vein thrombosis (DVT) is a common clinical condition. In the acute phase, it can lead to secondary complications such as acute pulmonary embolism (PE) and limb swelling, while in the chronic phase, it may result in post-thrombotic syndrome (PTS), posing significant health risks. Early mechanical thrombectomy can restore venous patency, alleviate symptoms, and reduce the incidence of PTS. AngioJet percutaneous mechanical thrombectomy (PMT) offers the advantages of rapid and efficient thrombectomy with fewer complications, making it widely used in clinical practice. However, there are currently no standardized guidelines at home or abroad regarding the choice of access route for PMT. This study was performed to compare the clinical outcomes and effects on venous valve function of antegrade versus retrograde AngioJet PMT for treating acute lower extremity DVT, aiming to explore the optimal surgical approach for thrombectomy.Methods A prospective, randomized controlled study was conducted, enrolling 96 patients with acute lower extremity DVT treated at the Department of Vascular Surgery, Beijing Jishuitan Hospital, Capital Medical University, from January 2022 to June 2024. Patients were divided into an antegrade group and a retrograde group based on the direction of operation and valve opening. Surgical outcomes and risks were evaluated for both groups, and factors influencing the 3-month postoperative venous patency rate were analyzed.Results A total of 92 patients were finally included, with 47 cases in the antegrade group (51.1%) and 45 cases in the retrograde group (48.9%), all treated with AngioJet PMT. Baseline characteristics showed no significant differences between the two groups (all P>0.05). In the antegrade group, 14 cases (29.8%) had thrombus interception by filters, with 7 cases (14.9%) being effective; 4 cases (8.5%) developed new or worsened PE. In the retrograde group, 18 cases (40.0%) had thrombus interception by filters, with 8 cases (17.8%) being effective; 5 cases (11.1%) developed new or worsened PE. No significant differences were observed between the two groups in these or other safety and laboratory variables (all P>0.05). The antegrade group had a higher proportion of intraoperative manual aspiration thrombectomy compared to the retrograde group (68.1% vs. 26.7%, P<0.001). However, there were no significant differences in thrombus grade Ⅲ clearance rate (61.7% vs. 68.9%), 3-month venous patency rate (93.6% vs. 91.1%), or other perioperative variables (all P>0.05). Regression analysis of factors affecting 3-month venous patency showed that immediate venous patency (OR=3.043, 95% CI=0.993-1.209) and radiation dose (OR=0.868, 95% CI=-0.001-0.000) in the antegrade group, as well as immediate venous patency (OR=2.333, 95% CI=0.655-0.980) in the retrograde group, were significantly associated with 3-month patency rate (all P<0.001). Regression analysis also showed a significant linear relationship between immediate venous patency and VCSS/Villalta scores in both groups (all P<0.001).Conclusion Both antegrade and retrograde AngioJet PMT procedures are equally safe and effective for treating acute lower extremity DVT. However, the risk of intraoperative thrombus detachment remains high, warranting the use of inferior vena cava filters to prevent fatal PE. Patients with immediate venous patency require standardized postoperative management and follow-up to prevent PTS.