Purpose The aim was to assess the role of catheter-directed thrombolysis (CDT) in improving patency of the treated venous segments and to examine the correlation of residual thrombus with post-thrombotic syndrome (PTS). Background Iliofemoral deep vein thrombosis (DVT) is associated with severe post-thrombotic morbidity when treated with anticoagulation alone. CDT allows early removal of thrombus and reduce valvular reflux and PTS. Patients and methods This prospective randomized controlled two-arm study was conducted on 42 patients with iliofemoral DVT. The patients were randomly allocated into two groups according to the intervention performed. Group A: CDT followed by oral anticoagulants [N=21 (50%)], group B: standard DVT therapy [N=21 (50%)]. The follow-up period was 24 months. Results Patients of group A complained of less pain at 10 and 30 days (P=0.02 and 0.04, respectively). Also, there was significant decrease in leg circumference in group A at 10 and 30 days (P=0.001 and 0.03, respectively). A total of three (15%) clinically relevant nonmajor bleeding complications were reported in the CDT group. Using CDTisassociatedwith lessPTSat sixthmonth,1year,and2years; six (27.3%),seven (31.8%), and nine (40.9%), respectively, as compared with group B; 11 (47.8%), 13 (56.5%), and 15 (65.2%), respectively (P=0.024, 0.017, and 0.035, respectively). Conclusion Addition of CDT in the treatment of acute iliofemoral DVT was safe and tolerated by most of the patients with better effect to reduce leg pain and circumference. It was considered a protecting weapon to prevent PTS and thereby improving the quality of life and was related to achievement of higher iliac vein patency and less reflux.