Background We tested the feasibility of ultrasound technology for generating pressurized intraperitoneal aerosol chemotherapy (usPIPAC) and compared its performance vs. comparator (PIPAC). Material and methods A piezoelectric ultrasound aerosolizer (NextGen, Sinaptec) was compared with the available technology (Capnopen, Capnomed). Granulometry was measured for water, Glc 5%, and silicone oil using laser diffraction spectrometry. Two- and three-dimensional (2D and 3D) spraying patterns were determined with methylene blue. Tissue penetration of doxorubicin (DOX) was measured by fluorescence microscopy in the enhanced inverted Bovine Urinary Bladder model (eIBUB). Tissue DOX concentration was measured by high-performance liquid chromatography (HPLC). Results The droplets median aerodynamic diameter was (usPIPAC vs. PIPAC): H20: 40.4 (CI 10–90%: 19.0–102.3) vs. 34.8 (22.8–52.7) µm; Glc 5%: 52.8 (22.2–132.1) vs. 39.0 (23.7–65.2) µm; Silicone oil: 178.7 (55.7–501.8) vs. 43.0 (20.2–78.5) µm. 2D and 3D blue ink distribution pattern of usPIPAC was largely equivalent with PIPAC, as was DOX tissue concentration (usPIPAC: 0.65 (CI 5-95%: 0.44–0.86) vs. PIPAC: 0.88 (0.59–1.17) ng/ml, p = 0.29). DOX tissue penetration with usPIPAC was inferior to PIPAC: usPIPAC: 60.1 (CI 5.95%: 58.8–61.5) µm vs. PIPAC: 1172 (1157–1198) µm, p < 0.001). The homogeneity of spatial distribution (top, middle and bottom of the eIBUB) was comparable between modalities. Discussion usPIPAC is feasible, but its performance as a drug delivery system remains currently inferior to PIPAC, in particular for lipophilic solutions.