Background: Tumor mRNA expression levels may have a promising role as potential predictive biomarkers for chemotherapy. Intraperitoneal (IP) chemotherapy provides sustained high local concentrations, and its efficacy has been shown in ovarian cancer and gastric cancer patients with peritoneal metastasis. We developed a regimen combining IP/intravenous(IV)/oral chemotherapy for the treatment of advanced gastric cancer patients with individualized chemotherapeutics according to mRNA expression. This multicenter phase III study evaluated the efficacy of individualized multi-route chemotherapy compared to standard systemic chemotherapy. Methods: Eligibility criteria included pathologically confirmed advanced gastric adenocarcinoma, and no prior chemotherapy. Patients were randomized 3:1 to an individualized arm (IN) and standard arm (ST). Randomization was stratified by center. Patients in individualized arm first underwent mRNA expression (BRCA1/TOPO1/TS) to choose sensltive chemotherapeutics from oxaliplatin/cisplatin/docetaxel/irinotecan/S-1 and then received individualized IP/IV/oral chemotherapy. The primary endpoint was overall survival (OS). Secondary endpoints were response rate, progression-free survival (PFS), and safety. Results: Between April 2013 and December 2015, 231 patients were enrolled, and 218 patients were included in the efficacy analysis. Baseline patient characteristics were balanced between the two arms. The median OS for IN and ST were 16.3 and 14.1 months, respectively (adjusted hazard ratio [aHR] 0.77, 95% confidence interval [CI] 0.61-0.98, p < 0.05). The overall response rate was 44.0% in the IN arm, and 33.9% in the ST arm (p < 0.05). Both regimens were tolerable. Conclusions: The primary analysis showed the statistical superiority of the individualized multi-route regimen. It suggested clinical efficacy of this regimen in patients with advanced gastric cancer. Clinical trial information: ChiCTR-IPR-15006201.