PurposeTo compare the safety and efficacy of histotripsy with cryoablation in a chronic human-scale normal porcine kidney model. Materials and MethodsEighteen female domestic swine were divided evenly into histotripsy and cryoablation treatment arms. A planned 2–3 cm diameter treatment was performed under ultrasound (histotripsy) or ultrasound and computed tomography (CT) guidance (cryoablation). Contrast-enhanced CT and serum blood analysis were performed immediately postprocedure and on day 7, with either immediate killing (n = 3) or continued survival to day 30 (n = 6), at which time contrast-enhanced CT, serum blood analysis, and necropsy were performed. Animal welfare, treatment zone appearance, procedure-related adverse events, and histopathology of the treatment zones and surrounding tissues were assessed. ResultsHistotripsy treatment zones (mean ±standard deviation diameters, 2.7 ± 0.12 × 2.4 ± 0.19 × 2.4 ± 0.26 cm; volume, 8.3 ± 1.9 cm3) were larger than cryoablation zones (mean diameters, 2.2 ± 0.19 × 1.9 ± 0.13 × 1.7 ± 0.19 cm; volume, 3.9 ± 0.8 cm3; P < .001). At 30 days, histotripsy and cryoablation treatment zone volumes decreased by 96% and 83% on CT, respectively (P < .001). Perirenal hematomas were present after 8 of 9 (89%) cryoablation (mean volume, 22.2 cm3) and 1 of 9 (11%, P < .001) histotripsy (volume, 0.4 cm3) procedures, with active arterial extravasation in 4 of 9 (44%) cryoablation and no histotripsy animals (P = .206). All 9 histotripsy animals and 5 of 9 (56%) cryoablation animals had collecting system debris (P = .042). Changes in serum creatinine were similar between the groups (P = .321). ConclusionsOther than a higher rate of bleeding after cryoablation, the safety and early efficacy of histotripsy and cryoablation were comparable for creating treatment zones in a chronic normal porcine kidney model.