The effect of preoperative immunonutrition intake on postoperative major complications in patients following cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) was assessed. The accuracy of C-Reactive Protein (CRP) for detecting postoperative complications was also analyzed. Patients treated within a peritoneal carcinomatosis program in which a complete or optimal cytoreduction was achieved were retrospectively analyzed. They were divided into two groups based on whether preoperative immunonutrition (IMN) or not (non-IMN) were administered. Clinical and surgical variables and postoperative complications were gathered. Predictive values of major morbidity of CRP during the first 3 postoperative days (POD) were also evaluated. A total of 107 patients were included, 48 belonging to the IMN group and 59 to the non-IMN group. In multivariate analysis immunonutrition (OR 0.247; 95%CI 0.071–0.859; p = 0.028), and the number of visceral resections (OR 1.947; 95%CI 1.086–3.488; p = 0.025) emerged as independent factors associated with postoperative major morbidity. CRP values above 103 mg/L yielded a negative predictive value of 84%. Preoperative intake of immunonutrition was associated with a decrease of postoperative major morbidity and might be recommended to patients with peritoneal carcinomatosis following CRS. Measuring CRP levels during the 3 first postoperative days is useful to rule out major morbidity.