Background: Intraperitoneal (IP) paclitaxel (PTX) provides sustained high local concentrations, and its efficacy has been shown in ovarian cancer. We developed a regimen combining IP PTX with S-1/PTX for the treatment of gastric cancer patients, and obtained promising results with a one-year overall survival (OS) rate of 78% in a phase II study. This multicenter phase III study evaluated the efficacy of IP PTX plus S-1/PTX compared to standard systemic chemotherapy. Methods: Eligibility criteria included pathologically confirmed gastric adenocarcinoma, peritoneal metastasis, and no or short-term (< 2 months) prior chemotherapy. Patients were randomized 2:1 to an IP (IP PTX plus S-1/PTX; IP PTX 20 mg/m², intravenous [IV] PTX 50 mg/m² on days 1 and 8, and S-1 80 mg/m²/day on days 1-14, q3 weeks) arm or a SP (S-1/cisplatin; IV cisplatin 60 mg/m² on day 8, and S-1 80 mg/m²/day on days 1-21, q5 weeks) arm. Randomization was stratified by center, having received prior chemotherapy, and the extent of peritoneal disease. The primary endpoint was OS. Secondary endpoints were response rate and safety. Results: Between October 2011 and November 2013, 183 patients were enrolled, and 164 patients were included in the efficacy analysis. Baseline patient characteristics were balanced between the two arms except for ascites. Of 45 patients with massive ascites (beyond the pelvic cavity), 38 (84%) were randomized to the IP arm and 7 (16%) to the SP arm. The median OS for IP and SP were 17.7 and 15.2 months, respectively (stratified log-rank test, p = 0.080; hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.49-1.04, p = 0.081). For a sensitivity analysis using a stratified Cox regression model, adjusting for the baseline ascites, the HR was 0.59 (95%CI 0.39-0.87, p = 0.0079). The overall response rate was 53% in the IP arm, and 60% in the SP arm (p = 1.0). Both regimens were tolerable, and there were no treatment-related deaths. Conclusions: The primary analysis did not show the statistical superiority of the IP regimen. The sensitivity analysis, considering the imbalance of ascites, suggested clinical efficacy of IP PTX in gastric cancer with peritoneal metastasis. Clinical trial information: UMIN000005930.