Background <p>Pressurized intraperitoneal aerosol chemotherapy (PIPAC) improves local drug delivery and has shown promising results for treating peritoneal surface malignancies (PSMs); however, comparative data on the performance of different PIPAC nozzles in disease-bearing models are limited.</p> Objective <p>This study aimed to evaluate the therapeutic efficacy of three PIPAC nozzles in a rabbit model of PSM.</p> Methods <p>Nine immunocompetent New Zealand rabbits received intraperitoneal injections of VX2 tumor cells to induce PSM. The animals were randomized into three groups (<i>n</i>&#xa0;=&#xa0;3) and treated with oxaliplatin-based PIPAC using CapnoPen^®, HurriChem™, or MCR-4 TOPOL^® nozzles on days 8, 15, and 21. Evaluations included the Peritoneal Cancer Index (PCI), tumor weight, histopathology (Peritoneal Regression Grading Score [PRGS]), imaging, and markers of proliferation (Ki-67) and apoptosis (TUNEL). The final results, including autopsy, were obtained on day 26.</p> Results <p>CapnoPen^® showed a trend toward improved tumor regression, with significantly lower PCI scores at euthanasia. After the third PIPAC, the mean PCI was lower in the CapnoPen^® group compared with MCR-4 TOPOL^® (6.33 vs. 13.3; <i>p</i>&#xa0;=&#xa0;0.041). Tumor weights were also lowest in the CapnoPen^® group. Mean PRGS values were 2.14 (CapnoPen^®), 2.75 (HurriChem™), and 3.49 (MCR-4), with a significant difference between CapnoPen^® and MCR-4 (<i>p</i>&#xa0;=&#xa0;0.033). All devices significantly reduced PCI compared with controls from a previous study (no chemotherapy: 21.6; <i>p</i>&#xa0;&lt;&#xa0;0.01).</p> Conclusion <p>This initial study suggests that the type of PIPAC nebulizer may influence therapeutic efficacy in a rabbit model with peritoneal metastasis, highlighting the need for further controlled studies to confirm these preliminary findings</p>