Background and Aims Iliac vein compression syndrome (IVCS) is a major cause of acute lower extremity deep vein thrombosis (DVT). Without timely treatment, it can lead to thrombus detachment, resulting in pulmonary embolism and increased mortality risk. Percutaneous mechanical thrombectomy, particularly using the AngioJet thrombectomy system, is a widely used thrombectomy method. The combination of AngioJet thrombectomy with iliac vein stent placement provides a novel treatment option for DVT associated with IVCS. This study was performed to evaluate the efficacy and safety of AngioJet thrombectomy combined with iliac vein stent placement in treating DVT with IVCS.Methods The clinical data of 120 patients with DVT and IVCS treated between April 2019 and October 2022 were retrospectively analyzed. Sixty patients underwent AngioJet thrombectomy combined with iliac vein stent placement (observation group), while another 60 patients received catheter-directed thrombolysis (CDT) combined with stent placement (control group). The clinical efficacy, outcomes (thrombus clearance grade, thrombolysis duration, venous patency score, hospitalization duration, urokinase dosage, thigh circumference difference, and calf circumference difference), Villalta scores at various time points before and after treatment, and adverse events (chest tightness, mild pulmonary embolism, bleeding at the catheter insertion site, and mild renal function impairment) were compared between the two groups.Results The overall efficacy rate in the observation group was significantly higher than that in the control group (98.33% vs. 86.67%, P=0.015). While there was no significant difference in thrombus clearance grade between the two groups (P>0.05), the observation group had significantly shorter thrombolysis duration, lower urokinase dosage, and shorter hospitalization time compared to the control group (all P<0.05). Before treatment, there were no significant differences in thigh circumference difference, calf circumference difference, or venous patency score between the two groups (all P>0.05). After treatment, the observation group had significantly better venous patency score and smaller thigh and calf circumference differences than the control group (all P<0.05). There was no significant difference in Villalta score between the two groups before treatment (P>0.05). Post-treatment Villalta scores showed a significant decreasing trend over time in both groups compared to pre-treatment scores (all P<0.05), but there were no statistically significant differences in Villalta scores between the two groups at 1, 6, and 12 months after treatment (all P>0.05). The total incidence of adverse events was not significantly different between the two groups (10.00% vs. 3.33%, P=0.143).Conclusion The use of AngioJet thrombectomy combined with iliac vein stent placement for the treatment of lower extremity DVT with IVCS can shorten thrombolysis and hospitalization duration, reduce thrombolytic drug dosage, and achieve better and safer outcomes, making it worthy of clinical application.