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Simple Summary: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy has been introduced in order to improve outcomes for selected patients with peritoneal surface malignancies. Although survival benefits have been widely reported in the literature, this treatment is still not accepted worldwide because of the potential high incidence of postoperative complications. The aim of this study was to record the morbidity and mortality rates and to evaluate the associated risk factors. In our experience, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy appeared as a safe and feasible procedure with good postoperative outcomes if performed in specialized centers. Further improvement of results could be achieved with better selection of patients. Background: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy may significantly improve survival for selected patients with peritoneal surface malignancies, but it has always been criticized due to the high incidence of postoperative morbidity and mortality. Methods: Data were collected from nine Italian centers with peritoneal surface malignancies expertise within a collaborative group of the Italian Society of Surgical Oncology. Complications and mortality rates were recorded, and multivariate Cox analysis was used to identify risk factors. Results: The study included 2576 patients. The procedure was mostly performed for ovarian (27.4%) and colon cancer (22.4%). The median peritoneal cancer index was 13. Overall postoperative morbidity and mortality rates were 34% and 1.6%. A total of 232 (9%) patients required surgical reoperation. Multivariate regression logistic analysis identified the type of perfusion (p ≤ 0.0001), body mass index (p ≤ 0.0001), number of resections (p ≤ 0.0001) and colorectal resections (p ≤ 0.0001) as the strongest predictors of complications, whereas the number of resections (p ≤ 0.0001) and age (p = 0.01) were the strongest predictors of mortality. Conclusions: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy is a valuable option of treatment for selected patients with peritoneal carcinomatosis providing low postoperative morbidity and mortality rates, if performed in high-volume specialized centers. [ABSTRACT FROM AUTHOR]