Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new laparoscopic administration of chemotherapy for peritoneal metastasis (PM). PIPAC is repeated every 5th week, and seems to stabilize or improve quality of life, and might improve survival. So far, PIPAC has been well tolerated. With this paper, we aim to highlight a potential severe adverse reaction, as we describe the first cases of severe peritoneal sclerosis (SPS) caused by PIPAC. Patients with isolated PM were included in a prospective PIPAC protocol. Following insufflation of normothermic CO2, laparoscopy was performed at an intraabdominal pressure of 12 mmHg. After peritoneal lavage and quadrant biopsies of the PM, the patients were treated with oxaliplatin 92 mg/m2 (flowrate 0.5 ml/s, maximum pressure of 200 per square inch). Treatment related toxicity was evaluated after 2 weeks. Response was evaluated histologically by the Peritoneal Regression Grading Score (PRGS) and cytologically by analysis of the lavage fluid. In a series of 24 PIPAC patients treated with oxaliplatin, two patients developed SPS. Patient one had a mucinous adenocarcinoma of the appendix with PM, the mean PRGS was reduced from 2.75 to 1.75 during the course of therapy. Patient two had an appendiceal goblet cell carcinoid with a dominating mucinous adenocarcinoma component with PM, the mean PRGS was reduced from 2.00 to 1.67. Repeated applications of PIPAC with oxaliplatin can lead to SPS.