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This prospective randomized multicenter study aims to evaluate the efficacy of extensive intraoperative peritoneal lavage followed by intraperitoneal chemotherapy (EIPL-IPC) on the overall 5-year survival of advanced gastric cancer patients with intraperitoneal free cancer cells without overt peritoneal metastasis (CY+/P−). The study also aims to determine the merit and reliability of EIPL-IPC therapy as a prophylactic strategy for peritoneal metastasis.Although the prognosis of advanced gastric cancer patients with CY+/P− is extremely poor, a suitable standard regimen for treating such patients has not yet been established.A total of 88 patients with CY+/P− from 1522 patients with advanced gastric cancer at multicenters were enrolled in this study and were randomly allocated to 3 groups: surgery alone group, surgery plus intraperitoneal chemotherapy (IPC) group, and surgery plus EIPL and IPC (EIPL-IPC) group. Prognostic significance of EIPL-IPC therapy was evaluated by Kaplan-Meier curves, and its value as an independent prognostic factor was assessed by univariate and multivariate analyses.The overall 5-year survival rate of the patients with EIPL-IPC was 43.8%, and this data were significantly better than that of the IPC group (4.6%, P < 0.0001) and the surgery alone group (0%, P < 0.0001). Among various recurrent patterns, the EIPL-IPC group had a significantly lower incidence of peritoneal recurrence than both of the other groups (P < 0.0001). Univariate and multivariate analyses revealed that EIPL was the most significant impact factor.The present study clearly revealed that EIPL-IPC therapy significantly improved the 5-year survival span of advanced gastric cancer patients with CY+/P−. Thus, EIPL-IPC therapy is strongly recommended as a standard prophylactic strategy for peritoneal dissemination.