Background: Cytoreductive surgery (CRS) combined with perioperative intraperitoneal chemotherapy (PIC) has demonstrated improved survival in selected patients with colorectal peritoneal carcinomatosis (CRPC). This treatment modality is associated with relatively high rates of perioperative morbidity and mortality. This study evaluated the clinical and treatment-related risk factors for perioperative morbidity and mortality in patients with CRPC who underwent CRS and PIC. Methods: Sixty-three consecutive patients who underwent CRS and PIC for CRPC were evaluated. Adverse events were rated from grades I to V with increasing severity. Clinical and treatment-related risk factors for grades III and IV/V morbidity were determined. Results: There were no perioperative deaths (0%). The grades III and IV morbidity rates were 14 and 17%, respectively. A peritoneal cancer index >12 (p = 0.019), transfusion >4 units (p = 0.028), number of peritonectomy procedures >3 (p = 0.013), left upper quadrant peritonectomy procedure (p < 0.001), and number of primary colonic anastomosis >1 (p = 0.004) were associated with grade IV morbidity on univariate analysis. Only left upper quadrant procedure was associated with grade IV morbidity on multivariate analysis (p = 0.002). Only number of primary colonic anastomosis >1 (p = 0.037) was associated with grade III morbidity on univariate analysis. This also was associated with grade III morbidity on multivariate analysis (p = 0.028). Conclusions: CRS and PIC has an acceptable risk of perioperative morbidity in carefully selected patients with CRPC. Patients who require extensive surgery have the highest risk for a severe adverse event. Preoperative evaluation of patients is essential to improve perioperative outcome.