Cytoreductive Surgery (CRS) ± Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is associated with a high incidence of postoperative morbidity. Our aim was to identify independent, potentially actionable perioperative predictors of major complications. We reviewed patients who underwent CRS ± HIPEC from June 2020 to January 2022 at a high-volume center. Postoperative complications were categorized using the Comprehensive Complication Index, with the upper quartile defining major complications. Multivariate logistic analysis identified predictive and protective factors. Of 168 patients, 119 (70.8%) underwent HIPEC. Mean Comprehensive Complication Index was 12.6 (12.7) and upper quartile cut-off was 22.6. Medical complications were more frequent but less severe than surgical (63% vs 18%). Forty-six patients (27.4%) comprised the "major complications" group (mean CCI 30.1 vs 6.3). Multivariate logistic regression showed that heart disease (RR 1.9; 95% CI: 1.1 to 3.3), number of anastomoses (RR 2.4; 95% CI:1.3 to 4.6) and first 24-h fluid balance (RR 1.1; 95% CI: 1.1 to 1.2), were independently associated as risk factors for major complications, while opioid-free anesthesia (RR 0.6; 95% CI: 0.3 to 0.9) and high preoperative hemoglobin (RR 0.9; CI 95%: 0.9 to 0.9) were independent-protective factors. Preoperative heart diseases, number of anastomoses and first 24h-fluid balance are independent risk factors for major postoperative complications, while high preoperative hemoglobin and opioid-free anesthesia are protective. Correction of anemia prior to surgery, avoiding positive fluid balance and incorporation of opioid-free anesthesia strategy are potential actionable measures to reduce postoperative morbidity.