This study evaluated whether D-dimer (DD) concentration analysis is a useful approach for noninvasive monitoring of clot lysis during catheter-directed thrombolysis (CDT) for deep vein thrombosis (DVT). DD levels have been found to be elevated during fibrinolytic therapy for DVT. Therefore, measuring the level of DD is a potential alternative method to assess the effect of fibrinolytic therapy. From January 2013 to March 2014, 32 patients with symptomatic acute DVT involving the iliac or femoral veins were treated using CDT. Urokinase was the thrombolytic agent. Demographics, procedural details, DD concentration, and thrombus score were recorded before and after the thrombolytic therapy. The peak DD concentration was 35.35 ± 11.18 μg/mL during CDT therapy, and the time-integrated DD concentration was 157.95 ± 69.46 μg·d/mL. The peak DD concentrations were higher in patients with substantial lysis compared with those in patients with minimal or no lysis (40 ± 0 versus 30.7 ± 14.57 μg/mL; P = 0.016). The time-integrated DD concentrations were also higher in patients with substantial lysis compared with those in patients with minimal or no lysis (194.14 ± 37.57 units versus 121.75 ± 75.93 units, P = 0.002). There was a moderate correlation (r = 0.57) between the peak DD level and the lysed clot volume. There was also a correlation between the time-integrated DD and clot lysis (r = 0.65). DD concentration analysis offers an alternative approach to noninvasive monitoring of venous clot lysis during CDT for DVT.