PURPOSE: The application of histotripsy, an emerging noninvasive, non-ionizing, and non-thermal tumor treatment, is currently limited by the inherent limitations of diagnostic ultrasound as the sole targeting modality. This study evaluates the feasibility and accuracy of cone beam computed tomography (CBCT) guidance for histotripsy treatments in an porcine model. MATERIALS AND METHODS: Histotripsy treatments were performed in the liver of seven healthy swine under the guidance of a C-arm CBCT system that was calibrated to the robotic arm of the histotripsy system. For each treatment, pseudotumors (small histotripsy treatments of 15 mm) were created using conventional US guidance to serve as targets for subsequent CBCT guided treatments. A pretreatment CBCT with intravenous contrast was acquired for each swine and the center of the pseudotumor was selected as the target. The robotic arm automatically aligned the transducer to the selected target location. Ultrasound based aberration offset correction was performed when possible, and a 25 mm diameter treatment was performed. A post-treatment CBCT with intravenous contrast was then acquired to evaluate coverage, treatment size, and distance between the pseudotumor target and actual treatment zone center. RESULTS: Treatments were technically successful and pseudotumors were completely covered in all seven treatments (7/7). The average treatment diameter was 39.3 ± 4.2 mm. The center-to-center distance between pseudotumor and actual treatments was 3.8 ± 1.3 mm. CONCLUSION: CBCT provides accurate targeting for histotripsy treatment . While future work is required to assess safety and efficacy in the presence of obstructions, the proposed approach could supplement ultrasound imaging for targeting.