Background: Intraperitoneal (IP) chemotherapy is a promising treatment option for gastric cancer with peritoneal metastasis. We previously reported the safety and efficacy of IP paclitaxel (PTX) plus S-1/PTX in phase I and II studies. S-1/oxaliplatin (SOX) showed non-inferiority to S-1/cisplatin in PFS, and is considered as a new standard regimen for the first-line treatment of advanced gastric cancer on an outpatient basis in Japan. We designed a new regimen combining IP PTX with SOX in order to maximize systemic effects as well as local effects in the peritoneal cavity. The recommended dose of IP PTX was determined to be 40 mg/m² in a phase I study. A phase II study of SOX plus IP PTX regimen was performed in gastric cancer patients with peritoneal metastasis. Methods: Gastric cancer patients with peritoneal metastasis confirmed by diagnostic imaging, laparoscopy or laparotomy were enrolled. PTX was administered intraperitoneally at 40 mg/m² on days 1 and 8. Oxaliplatin was administered intravenously at 100 mg/m² on day 1, and S-1 was administered at 80 mg/m²/day for 14 consecutive days, repeated every 21 days. The primary endpoint was the 1-year overall survival (OS) rate. Secondary endpoints were response rate, negative conversion rate on peritoneal cytology and safety. Results: Sixty patients were enrolled and fully evaluated for OS and toxicity. The median number of courses was 10 (range 1-19). The 1-year OS rate was 71% (95% CI, 58-81%). The overall response rate was 67% (95% CI, 22-96%) in 6 patients with target lesions. Cancer cells ceased to be detected by peritoneal cytology in 35 (75%) of 47 patients. The incidences of grade 3/4 hematological and non-hematological toxicities were 55% and 44%, respectively. The frequent grade 3/4 toxicities included neutropenia (50%), leukopenia (27%), anemia (18%) febrile neutropenia (12%) and anorexia (12%). Catheter obstruction and infection of the peritoneal implantable port were observed in one patient each. There were no treatment-related deaths. Conclusions: Combination chemotherapy of SOX plus IP PTX regimen is well tolerated and active in gastric cancer patients with peritoneal metastasis. Clinical trial information: UMIN000012834.