Background Incomplete cytoreduction (IC) is one of the main prognostic factor in pseudomyxoma peritonei (PMP). We evaluated the ability of preoperative Ca125, CEA, and Ca19-9 to predict IC and prognosis in PMP. Methods One hundred fifty-six cases elected candidate to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy from 1996 to 2011 were included in the study. We assessed the: (1) optimal cut-off values for circulating Tumor markers (CTM) in predicting IC (residual disease >2.5mm) using receiver-operating characteristics (ROC); (2) discriminant power of CTM and risk prediction models for IC by calculating the area under ROC curve (AUC-ROC); (3) prognostic factors using Cox proportional-hazard model. Results Optimal cut-offs were 125U/ml for Ca125, 18ng/ml for CEA, and 89U/ml for Ca19-9. The AUCs-ROC were 0.76, 0.68, and 0.69 for Ca125, CEA, and Ca19-9, respectively. The addition of CTM to risk prediction model that considered preoperative clinicopathological factors increased marginally the AUC-ROC (0.80-0.84). Ca125>125U/ml, Ca19-9>89U/ml independently affected overall survival. Conclusions Preoperative CTMs were reasonable but not perfect discriminators of IC. Moreover, Ca125 and Ca19-9, using new cut-off values, were proven to be new strong prognostic factors that overcome the value of disease extension and histological subtype. J. Surg. Oncol. 2013;108:1-8. (c) 2013 Wiley Periodicals, Inc.