PURPOSE: The hypothesis of this study was that histotripsy, an ultrasound therapy that disrupts tissue mechanically through the action of bubble clouds, increases the short-term rate of acute thrombus clearance for catheter-directed thrombolysis (CDT) in an animal model. MATERIALS AND METHODS: Thrombi formed in the femoral vein of pigs were treated with CDT, histotripsy, or CDT and histotripsy (histotripsy+). Ultrasound (B-mode and color Doppler) and contrast fluoroscopy imaging data were scored by 4 observers for semiquantitative evaluation of each arm with ordinal regression models. Further, B-mode images were manually annotated by 3 observers to quantify the thrombus clearance rate. RESULTS: A total of 27 thrombi (2.0 cm [SD ± 0.4] in length) in 27 animals were considered in this study (N = 8 for CDT, N = 9 for histotripsy, and N = 10 for histotripsy+). The mean treatment duration was 20.2 minutes (SD ± 1.3). The ordinal regression models indicated that the thrombus clearance rate increased for histotripsy+ relative to CDT based on B-mode and color Doppler but not fluoroscopy (P = .015, P = .001, and P = .900, respectively). Manual annotation of B-mode images denoted that histotripsy+ had an increased thrombus clearance rate relative to CDT and histotripsy (P = .001 and P = .022, respectively). Petechial hemorrhage was present in the perivascular soft tissue for 2 cases with histotripsy and 1 case with histotripsy+. CONCLUSIONS: The clearance of acute thrombus was similar for treatment with CDT or histotripsy. Combining these individual approaches further increased the rate of thrombus clearance based on multiple imaging metrics.