Background: The prognosis of gastric cancer with serosal invasion is extremely poor. Despite various perioperative adjuvant therapies, peritoneal recurrence is still difficult to control. Since the clinical efficacy of intraperitoneal (IP) paclitaxel (PTX) was suggested for the treatment of gastric cancer with peritoneal metastasis and positive cytology, IP PTX is a promising strategy for curatively resectable gastric cancer with serosal invasion. This multicenter, phase II study evaluated the efficacy and safety of IP PTX plus S-1/PTX for this target. Methods: Eligibility criteria included pathologically confirmed gastric adenocarcinoma with serosal invasion, but no peritoneal or distant metastases. Patients received three courses of preoperative IP PTX plus S-1/PTX (IP PTX 20 mg/m², intravenous PTX 50 mg/m² on days 1 and 8, and S-1 80 mg/m²/day on days 1-14, q3 weeks) followed by D2 gastrectomy, and they then received three courses of IP PTX plus intravenous PTX postoperatively. The primary endpoint was the proportion of the completion of protocol treatment (% protocol completion). Secondary endpoints were safety, overall survival, and the response rate (RR). The sample size was calculated to be 50 cases, under the hypothesis of expected % protocol completion of 80% and threshold % protocol completion of 60% with one-sided testing at the 2.5% significance level and power of 80%. Results: Between May 2014 and August 2016, 51 patients were enrolled. Among the 51 eligible patients with a median age of 66 years, 41 completed the protocol treatment (80.4% completion; 95% confidence interval 66.9–90.2%, p = 0.0016). During perioperative chemotherapy, grade 3/4 neutropenia occurred in 31.4%, and grade 3/4 non-hematological adverse events occurred in 19.6%. The incidence of adverse events related to surgery was 19.1%. There were no treatment-related deaths. Follow-up for long-term survival is continuing. The clinical RR of preoperative chemotherapy was 71.4% (5/7). The pathological RR (residual tumor < 2/3) was 68.1% (32/47). Conclusions: Perioperative IP PTX plus S-1/PTX is a safe and promising treatment for gastric cancer with serosal invasion. Clinical trial information: UMIN000013109.