Background: peritoneal mesothelioma (PM) is a rare and rapidly fatal neoplasm with an estimated survival of one year. The introduction of cytoreductive surgery with hyperthermic intraperitonal chemotherapy (CRS + HIPEC) has greatly improved overall survival rates. Many chemotherapeutic agents have been used in HIPEC therapy but nonetheless without difference in terms of patient survival. The aim of the study was to evaluate the prognostic impact of the different cytotoxic agents used in HIPEC to treat PM. Methods: from 1989 to 2014, 260 patients with PM were treated with CRS + HIPEC in 20 tertiary French centers and prospectively included in the RENAPE database. Inclusion criteria were age ≤ 80, performance status ≤ 2, no significant comorbidities and no extraperitoneal metastases. Results: 5 cytotoxic agents (CA) were used for HIPEC (Cisplatin (C), Doxorubicin (D), Mitomycin (M), oxaliplatin (O), irinotecan(I)) including 6 combination regimens (C, C+D, C+M, M, O, O+I). Regimen did not influence postoperative survival. But, regimen that use 2 CA (C+D, C+M, O+I) improve overall survival compared to regimen using 1 CA (C, M, O), P = 0.03 HR[95%CI] = 0.54 [0.31-0.95]. No difference was found according to major complications (Grade ≥ 3) between the 2 groups. The 2 groups were comparable according to median age, gender, neoadjuvant chemotherapy, asbestos exposure, CC0 resection, follow up, histologic subtypes, except for median PCI which was higher in 1 CA group (15) than in 2 CA group (19) (P = 0.006). In CC0 patients overall survival was still improved in 2 CA group versus 1 CA group (P = 0.01, HR[95%CI] = 0.34[0.14-0.83]). Conclusions: CRS + HIPEC using 2 CA drugs seems to be associated with an improvement in overall survival in patients with PM, in particular when given to patients with high PCI. No difference was found in term of postoperative complication between HIPEC using 2 CA versus 1 CA.