Peritoneal mesothelioma (PM) is a rare disease, with a poor prognosis. We decided to prospectively evaluate the prognostic impact and the morbimortality of cytoreductive surgery combined with intraperitoneal hyperthermic perfusion in the treatment of this clinical entity. Sixty one patients with PM (31 males and 30 females) were enrolled onto a Phase II multicentric clinical trial. The mean age was 51 years (range: 24-72). CRS was performed with peritonectomy procedures. The closed, opened and semi-closed abdomen techniques were employed for IPHP using cisplatin plus mitomycin-C or cisplatin and doxorubicin for 60/90 minutes under hyperthermic conditions (42.5 degrees C). One patient was operated on twice because of disease recurrence. Mean follow-up was 20 months (range: 0.1-76). Forty six (74%) patients were optimally cytoreduced. Five-year overall and 5 yr progression-free survivals were 54% and 37%, respectively. Completeness of cytoreduction was significantly associated with outcome. Twenty Grade III complications occurred in 14 (23%) patients and the most frequent one was digestive fistula/perforation (11%). No treatment-related mortality was recorded. CRS + IPHP was proven to be acceptable in terms of morbidity and mortality in patients with PM and suggest a positive impact on outcome. Further prospective controlled studies are warranted to confirm these results.