Background: Peritoneal metastasis is detected as any part of the metastasis/recurrence pattern in most stage III patients after radical surgery and appears to be the most life-threatening type of metastasis in patients with advanced gastric cancer. Previous studies have suggested that the molecular detection of cancer-specific carcinoembryonic antigen (CEA) mRNA levels in the peritoneal lavage has superior value for postoperative peritoneal recurrence in patients with advanced gastric cancer. The efficacy of intraperitoneal (IP) chemotherapy has been shown in gastric cancer patients with peritoneal metastasis. Methods: Eligibility criteria included pathologically confirmed stage III gastric adenocarcinoma after radical surgery, and no prior chemotherapy. Patients were first divided into CEA-positive group and CEA-negative group according to the CEA mRNA lever in the peritoneal lavage, and then in each group patients were randomized 1:1 to intraperitoneal (IP) arm and intravenous (IV) arm. Patients in IP arm received 2 cycles intraperitoneal docetaxel with oral S-1 and 4 cycles intravenous docetaxel with oral S-1, while patients in IV arm received 6 cycles intravenous docetaxel with oral S-1. The primary endpoint was 1-year disease-free survival rate (1-year DFS rate). Secondary endpoints were disease-free survival, overall survival, and safety. Result: Between April 2015 and June 2016, 161 patients were enrolled and 158 patients included in the efficacy analysis. 65 patients had positive CEA mRNA in peritoneal lavage and 93 had negative CEA mRNA. Baseline patient characteristics were balanced between IP arm and IV arm in both CEA-positive group and CEA-negative group. The 1-year DFS rate for CEA-positive group and CEA-negative group were 41% and 89%, respectively (p < 0.01). In CEA-negative group, the 1-year DFS rate for IP arm and IV arm were 86% and 89%, respective (P = 0.720). In CEA-positive group, the 1-year DFS rate for IP arm and IV arm were 66% and 41%, respective (P = 0.035). Both regimens were tolerable. Conclusion: The primary analysis showed the statistical superiority and clinical efficacy of the multi-route (intraperitoneal/intravenous/oral) regimen for patients with positive CEA mRNA in peritoneal lavage. It suggested clinical efficacy. Clinical trial information: ChiCTR-IPR-15006202.