BACKGROUND: Currently, no tumor-node-metastasis (TNM) staging system exists for patients with diffuse malignant peritoneal mesothelioma (DMPM). The primary objective was to formulate a clinicopathological staging system through the identification of significant prognostic parameters. METHODS: Eight international institutions with prospectively collected data on patients who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy contributed to the registry. Two hundred ninety-four patients had complete clinicopathological data and formed the basis of this staging project. RESULTS: Peritoneal cancer index (PCI) was categorized into T1 (PCI 1-10), T2 (PCI 11-20), T3 (PCI 21-30), and T4 (PCI 30-39). Twenty-two patients had positive lymph nodes (N1) and 12 patients had extra-abdominal metastases (M1). The survival for patients with T1 (PCI 1-10) N0 M0 was significantly superior to the other patients. This group of patients is therefore designated as Stage I. The survival of patients with T2 (PCI 11-20) and T3 (PCI 21-30), in absence of N1 or M 1 disease, was similar. This group of patients was categorized as Stage II. The survival of patients with T4 (PCI 30-39), N 1, and/or M1 was similarly poor. This group of patients was therefore categorized as Stage III. Three prognostic factors were independently associated with survival in the multivariate analysis: histological subtype, completeness of cytoreduction, and the proposed TNM staging. The 5-year survival associated with Stage I, II, and III disease was 87%, 53%, and 29%, respectively. CONCLUSIONS: The proposed TNM staging system resulted in significant stratification of survival by stage when applied to the current multi-institutional registry data. Cancer 2011;117:1855-1863.