Background: At present, there is no standard chemotherapy regimen for advanced gastric cancer (AGC), and there is no consensus whether the three-drug combination is better than two-drug combination in first-line treatment. Both of XELOX regimen and EOX regimen are widely recommended as firs-line chemotherapy regimens for AGC. In this EXELOX trial, we aimed to compare the efficacy and safety of EOX and XELOX regimens. Methods: EXELOX is an open-label, multicenter, prospective, randomized phase III trial that enrolled 448 previously untreated patients with histologically confirmed advanced gastric adenocarcinoma from 7 hospitals in China. Patients were randomly assigned (1:1) to receive XELOX regimen (oxaliplatin 130mg/m² d1; xeloda 1000mg/m² bid d1-14) or EOX regimen (epirubicin 50mg/m² d1; oxaliplatin 130mg/m² d1; xeloda 1000mg/m² bid d1-14) in this study. Treatment was repeated every 3 weeks until disease progression, intolerable toxicity, patient death, withdrawal of informed consent, or up to eight cycles, followed by xeloda single-agent maintenance. We stratified randomization by Eastern Cooperative Oncology Group status, extent of disease(locally advanced/metastatic) and clinical trial center. Patients and clinicians were not masked to the allocated treatment. The primary endpoint was progression-free survival (PFS) on an intention-to-treat basis with a non-inferiority upper margin of 1.3 for the hazard ratio (HR). The clinical trial was a non-inferiority study that was registered with ClinicalTrials.gov, Number NCT02395640. The study is ongoing, but no longer recruit new participants. Results: Between Apr 10,2015 and Aug 20,2020, a total of 448 AGC patients were randomized to receive XELOX (n = 222) or EOX (n = 226). In ITT basis, the median PFS was 5.0 months (95%CI 4.5-6.0) in XELOX group and 5.5 months (95%CI 5.0-6.0) in EOX group (HR 0.989, 95%CI 0.812-1.203; P_{non-inferiority}= 0.0032). In Per-protocol population (n = 428), the median PFS was 5.0 months (95%CI 5.0-6.0) in XELOX group and 5.5 months (95%CI 5.0-6.0) in EOX group (HR 0.983, 95%CI 0.807-1.198; P_{non-inferiority}= 0.0028). The incidence of grade 3-4 adverse events (AEs) was 42.2% (90/213) in XELOX group and 72.5(156/215) in EOX group (p= 0.001). The most common grade 3-4 AEs were neutropenia (affecting 13.1% (28/213) in XELOX group and 48.4%(104/215) in EOX group (p= 0.000). The incidence of chemotherapy dose reduction was 35% (75/213) in XELOX group and 55% (120/215) in EOX group(p= 0.009). One treatment-related death (lung infection) was observed in EOX group, and none in XELOX group. Conclusions: XELOX regimen is noninferior to EOX regimen in PFS with a better safety profile as first-line treatment for AGC patients, therefore XELOX is a more favorable choice and might be one of the standard first-line chemotherapy regimens. Clinical trial information: NCT02395640