Background <p>Low pneumoperitoneum pressure (LPP) lowers the incidence of CO₂ embolisms in minimally invasive liver resections (MILR), while higher pneumoperitoneum pressure (HPP) reduces intraoperative blood loss. This contradiction necessitates careful pressure management especially in major liver resections where intraoperative blood loss greatly impacts postoperative outcome.</p> Methods <p>In this randomized non-inferiority trial, adults undergoing elective MILR for any indication will be recruited in alignment with inclusion and exclusion criteria. After given informed consent, eligible patients will be randomized to either low (≤10 mmHg) or high (≥14 mmHg) pneumoperitoneum pressure during parenchymal transection. Blood, peritoneal biopsies, and liver tissue will be sampled to evaluate intraoperative tissue damage. Sample size (<i>n</i> = 66 patients per group) is calculated based on the current literature. The primary study endpoint is intraoperative blood loss during the parenchymal transection phase. Secondary endpoints include CO₂ embolisms, intraoperative tissue damage, operation time, morbidity, mortality, and duration of hospitalization.</p> Discussion <p>Minimizing intraoperative blood loss in MILR is a clinically relevant problem, which greatly impacts the procedure’s safety and influences the patient’s morbidity and mortality. HPP, exerting counter pressure to the vascular pressure, serves for bleeding control in MILR. The risk of CO₂ embolism, arising from the combination of high intra-abdominal pressure and low central venous pressure, favors the use of LPP. The proposed trial aims to assess the non-inferiority of LPP compared to HPP during the parenchymal transection phase of MILR.</p> Trial registration <p>ClinicalTrials.gov NCT06770803. First Submitted: 2024-12-30, First Submitted that Met QC Criteria: 2025-01-07, First Posted: 2025-01-13.</p>