Background: Cytoreductive surgery (CRS) combined with perioperative intraperitoneal chemotherapy (PIC) has demonstrated improved survival in selected patients with pseudomyxoma peritonei (PMP). However, this aggressive treatment modality has been consistently associated with variable rates of perioperative mortality between 0% and 18% and morbidity between 30% and 70%. This study evaluates the clinical and treatment-related risk factors for perioperative morbidity and mortality in PMP patients who underwent CRS and PIC. Materials and Methods: A total of 145 consecutive CRS and PIC procedures for PMP performed between January 1996 and March 2009 were evaluated. The association of 12 clinical and 20 treatment-related risk factors with grades III and IV/V morbidity were assessed by univariable and multivariable analysis. Results: The mortality (grade V) rate was 3%. The morbidity rates of grades III and IV were 23% and 22%, respectively. Eight factors were associated with grade IV/V morbidity on univariable analysis: Peritoneal cancer index ≥21 (P = .034), ASA score ≥3 (P = .003), operation duration ≥10 h (P < .001), left upper quadrant peritonectomy procedure (P = .037), colonic resection (P = .012), ostomy (P = .005), ileostomy (P = .012), and transfusion ≥6 units (p = 0.011). Multivariable analysis showed 2 significant risk factors for grade IV/V morbidity: ASA ≥ 3 (P = .006) and an operation length ≥10 h (P < .001). Conclusions: CRS and PIC has an acceptable rate of perioperative mortality and morbidity in selected patients with PMP. Patients with bulky disease who undergo a long operation are at a particularly high risk of a severe adverse event.