Background: Major morbidity (MM) after cytoreductive surgery with heated intraperitoneal chemotherapy (CRS/HIPEC) is associated with worsening of disabilities and length of the hospital stay. This study aimed to identify MM prognostic factors and to measure its impact on oncological outcomes. Methods: A post-hoc analysis of a prospective cohort of 734 patients with peritoneal metastasis (PM) from 2006 to 2015 was undertaken. Five hundred and two patients who had complete CRS and HIPEC for PM were included. Results: Major morbidity was identified in 31% (156/502) of CRS/HIPEC procedures, including 67 hemorrhagic complication (13.3%), 87 anastomotic leaks (17.4%), 121 reoperation (24.1%), and 65 pulmonary complication (12.9%). The multivariate predictors of MM were American Society of Anesthesiologists (ASA) score (ASA 3 vs. 1-2, 0R 95%CI: 3.58 [1.54 – 8.34]), origin of PM colorectal adenocarcinoma vs. other, OR 95%CI: 1.62 [1.06 – 2.48]), type of HIPEC drug (oxaliplatin vs. other, OR 95%CI: 2.85 [1.28 – 6.32]), number of anastomosis (no vs. at least 1, HR 95%CI: 1.85 [1.19 – 2.88]), blood transfusion (OR 95%CI: 1.84 [1.05 – 3.23]) and length of surgery longer than the median value (OR 95%CI: 1.88 [1.22 – 2.91]). The in-hospital mortality rate for the entire cohort was 1.7% (9/502). Rate of adjuvant chemotherapy after CRS/HIPEC was comparable between the two groups (70.3% vs. 72.4%, p = 0.64). The median duration of follow-up was 18 months. The MM group had worst OS and DFS comparing non-MM (Hazard ratio and 95% confidence interval at 3.48 [1.90 ; 6.35] and 1.91 [1.43 ; 2.57], respectively). Conclusions: Major morbidity after CRS/HIPEC for peritoneal metastasis is a source of significant reoperation and longer hospital and intensive care unit stay; with a decrease in overall survival and disease free survival even after complete CRS. Preoperative ASA score, number of anastomoses, colorectal origin of PM, HIPEC with oxaliplatin, blood transfusion and length of surgery are independent predictors of MM for CRS/HIPEC patients.