Background: About half of patients with serosa-invasive gastric cancer develop peritoneal recurrence and die of this disease even if curative resections performed. This prospective phase II study was performed to assess the efficacy and safety of hyperthermic intraperitoneal chemotherapy (HIPEC) with three anticancer drugs in patients with curative resection of clinically T3 or T4 serosa-invasive advanced gastric cancer. Methods: Patients age 75 years or younger with curative resection of clinically T3 or T4 advanced gastric cancer were eligible for this nonrandomized phase II trial. After the curative resection of gastric cancer with D2 lymph node dissection, HIPEC was carried out for 30 minutes with 50mg of CDDP, 10mg of MMC, and 1000mg of 5-FU in 5 L saline maintained at 42-43C°. Patients were given an adjuvant S-1 treatment after surgery. Primary endpoint of this study was overall survival. Second end points included safety and recurrence rate. Results: A total of 50 patients were eligible between January 2002 and December 2010. Pathologically, 12 patients had sub-serosal invasion (pT2(ss)), 35 patients had serosal invasion (pT3), and 3 patients had adjacent organ invasion (pT4). Median follow-up period was 52 months (12-104 months). Overall 5-year survival rate in all eligible patients was 89.9%. Overall 5-year survival rate in patients with stage IB (n=4), stage II (n=12), stage IIIA (n=18), or stage IIIB (n=16) was 100%, 100%, 90.9%, or 76.2%, respectively. Only one patient (2.0%) had peritoneal recurrences. Four patients (8.0%) with pN2 had lymphatic recurrences. A total of 13 patients had postoperative complications such as minor pancreatic fistula (Grade A) (10.0%), abdominal abscess (4.0%), leakage of the anastomosis (8.0%), and pneumonia (6.0%). All patients recovered without any surgical interventions. None of patients needed for the treatment in the Intensive Care Units after HIPEC. Conclusions: Intra-operative HIPEC with three anticancer drugs following curative resection of advanced gastric cancer improves overall survival with an inhibition of peritoneal recurrence and an acceptable morbidity.