Background: Peritoneal carcinomatosis is challenging to treat, with poor prognosis. Although pressurized intraperitoneal aerosol chemotherapy (PIPAC) and hyperthermal PIPAC (HPIPAC) aim to improve patients’ quality of life, there is a potential risk of antineoplastic drug exposure to healthcare workers during surgery. This study evaluates the risk of oxaliplatin exposure among healthcare workers during PIPAC and HPIPAC compared to systemic intravenous chemotherapy (IV). Methods: Oxaliplatin was administered to a swine model via IV, PIPAC, and HPIPAC in the operating room. Surface samples (n = 484) were collected from the operating room and personal protective equipment (PPE), while air samples (n = 144) were taken near the respiratory tract. Platinum, as an indicator of oxaliplatin, was measured using inductively coupled plasma mass spectrometry (ICP-MS). Results: Platinum was undetectable in 98.6% of the air samples, except one PIPAC leakage case. Surface contamination occurred in 8.7% of room samples and 13.9% of PPE, with gloves being most affected.Platinum contamination was also found on instruments like endoscope cameras and injectors, and cross-contamination on floors and injectors before PIPAC indicated suboptimal cleaning. No platinum was detected in the experimenter’s blood and urine. Conclusion Airborne platinum exposure was minimal when no drug leakage occurred, but surface contamination, particularly on gloves and instruments, highlighted the need for stringent protective measures to reduce occupational exposure risk. Although the possibility of inhalation exposure was low and there are no legal exposure standards for oxaliplatin, precautions should be taken to avoid potential exposure.