Patients with iliofemoral deep venous thrombosis suffer the most severe postthrombotic morbidity. Techniques that effectively remove thrombus from the venous system eliminate venous obstruction and potentially preserve valvular function. This will likely reduce or avoid the postthrombotic syndrome and improve long-term quality of life. To evaluate whether catheter-directed thrombolysis is associated with improved quality of life compared with anticoagulation alone and whether outcome in the thrombolysis group is related to lytic success, 98 patients with iliofemoral deep venous thrombosis who were treated at least 6 months earlier were identified and queried with a validated health-related quality-of-life questionnaire. Sixty-eight patients were identified through the Venous Registry (a national, multicenter venous registry) and were treated with catheter-directed thrombolysis with urokinase, and 30 patients were identified by means of medical record review and were treated with anticoagulation alone. All patients were candidates for thrombolysis; however, the treatment decision was made according to physician preference. The two treatment groups did not differ significantly in average time between the reference hospitalization and first contact. No difference was found in physical functioning and well-being between the groups before the development of deep venous thrombosis. Following treatment, patients receiving catheter-directed thrombolysis reported better overall physical functioning, less stigma, less health distress, and fewer postthrombotic symptoms compared to those patients treated with anticoagulation alone. Within the thrombolysis group, successful lysis correlated with health-related quality of life. Catheter-directed thrombolysis for the management of patients with iliofemoral deep venous thrombosis significantly improves health-related quality of life compared to similar patients treated with anticoagulation alone. Improved quality of life is related to successful thrombolysis. These data offer a compelling argument for a prospective randomized study.