Abstract: Venous thromboembolism is a major source of morbidity worldwide, and the degree of intervention depends on the likelihood of sequalae. Iliofemoral thrombi can migrate to the pulmonary circulation, which has a high associated risk of mortality. The frontline treatment for deep vein thrombosis is recanalization with a catheter-directed fibrinolytic administered over the course of several hours. Prolonged exposure to fibrinolytic carries an increased risk of undue bleeding. Further, mature venous thrombi contain components that are resistant to thrombolysis. Ultrasound has been investigated as both a direct means of achieving recanalization via mechanical ablation of thrombi or as an adjuvant therapy that enhances the efficacy of a lytic. Sonothrombolysis relies on bubble oscillations caused by an ultrasound pressure wave to diffuse lytic into the thrombus and to promote fibrinolysis. Histotripsy relies on ultrasound-induced nucleation of bubble clouds to liquefy tissue in situ. Because bubble activity is common to histotripsy and sonothrombolysis, histotripsy combined with a lytic is hypothesized to reduce the overall clot burden by erythrocyte fractionation (hemolysis) and increased lytic activity (fibrinolysis). In vitro studies were performed in a venous flow phantom to gauge the degree of hemolysis and fibrinolysis for clots exposed to histotripsy and lytic. Overall treatment efficacy was assessed via clot mass loss. Studies here indicated hemolysis and fibrinolysis contributed equally to thrombolytic efficacy for this combination therapy. Secondary analyses demonstrated the bubble cloud acts equally to promote hemolysis and fibrinolysis. These results show that histotripsy adjuvant to lytic therapy can reduce clot burden through multiple mechanisms.