Cytoreductive surgery and intraperitoneal (i.p.) chemotherapy constitute a curative treatment option in mucinous peritoneal surface malignancies of intestinal origin, but treatment outcome is highly variable and the search for novel therapies is warranted. Immunotoxins are attractive candidates for targeted therapy in the peritoneal cavity because of direct cytotoxicity, distinct mechanisms of action and tumor cell selectivity. The MOC31PE immunotoxin targets the tumor-associated adhesion protein EpCAM (Epithelial Cell Adhesion Molecule), and has been administered safely in early clinical trials. In our work, the efficacy of i.p. administration of MOC31PE alone and together with mitomycin C (MMC) was investigated in unique animal models of human mucinous peritoneal surface malignancies. In initial model validation experiments, clear differences in efficacy were demonstrated between MMC and oxaliplatin, favoring MMC in five investigated tumor models. Subsequently, MOC31PE and MMC were given as single i.p. injections alone and in combination. In the PMCA-2 model, moderate growth inhibition was obtained with both drugs, while the combination resulted in at least additive effects; whereas the PMP-2 model was highly sensitive to both drugs separately and in combination and intermediate sensitivity was found for the PMCA-3 model. Furthermore, results from ex vivo experiments on freshly obtained mucinous tumor tissue from animals and patients suggested that classic mechanisms of immunotoxin activity were involved, i.e., inhibition of protein synthesis and induction of apoptosis. The present results suggest that adding MOC31PE to MMC-based i.p. chemotherapy should be further explored for EpCAM-expressing peritoneal surface malignancies, and a phase I trial is in preparation.Mucinous peritoneal surface malignancies of intestinal origin encompass a range of clinical presentations, from the clinically benign manifestation pseudomyxoma peritonei (PMP) to aggressive mucinous peritoneal carcinomatosis from colorectal cancer. Histopathological presentation varies, with increasing cellular atypia, high epithelium to mucin ratio and signet ring cell differentiation being associated with an aggressive phenotype. The treatment is, regardless of histology, aimed at complete surgical removal of all visible tumor deposits followed by chemotherapy, typically some type of perioperative intraperitoneal (i.p.) chemotherapy, often supplemented with postoperative systemic chemotherapy. Prognosis is highly dependent on histopathological subtype, and particularly in peritoneal mucinous carcinomatosis (PMCA), the search for more efficacious chemotherapy regimens is warranted. [1][2][3] Although the benefit of cytoreductive surgery is well documented in mucinous peritoneal surface malignancies, the optimal chemotherapeutic strategy has not been proven. [2][3][4] Several drug combinations and delivery strategies are currently being pursued, mostly in early clinical trials, while preclinical assessment of drug efficacy has been impeded by lack o...