Background: Preoperative chemotherapy for initially unresectable locally advanced gastric cancer is thought to downsize tumors for curative resection and there upon prolong survival, but there is no best recommended regimen. We assessed the effectiveness of EOX (capecitabine, oxaliplatin and epirubicin) compared with XELOX (capecitabine and oxaliplatin) as preoperative chemotherapy for initially unresectable locally advanced gastric cancer. Methods: This is a prospective observational study. The trial was registered on ClinicalTrials.gov (NCT02192983). Patients with unresectable locally advanced gastric cancer were performed EOX regimen or XELOX regimen at the discretion of the investigators. They were assessed for response every 2 cycles by CT (computed tomography) scan. A multidisciplinary team reassessed resectability after 4 cycles. If disease became resectable, radical surgery would be performed within 4-6 weeks after the last treatment cycle. The primary endpoint was the response rate. Secondary end points included the R0 resection rate, survival and adverse events. Results: From November 2008 to May 2015, 242 patients were enrolled; 112 of them were assigned to EOX regimen and 130 to XELOX regimen. The response rates were 33.0% and 33.8% respectively in EOX group and XELOX group (P= 0.997). After 4 cycles of chemotherapy, 63 patients (56.3%) in EOX group and 81 patients (62.3%) in XELOX group received radical operation (P= 0.408). There was no significant difference in progress-free survival (PFS, 12.0m vs. 15.4m, P= 0.925) and overall survival (OS, 25.7m vs. 29.0m, P= 0.783) in two groups. In addition, more adverse effects occurred in EOX group, such as more leucopenia (22.3% vs. 10.0%, P= 0.014), neutropenia (23.2% vs. 11.5%, P= 0.025), fatigue (11.6% vs. 3.8%, P= 0.041) and vomiting (10.7% vs. 2.3%, P= 0.015). Conclusions: For unresectable locally advanced gastric cancer patients, XELOX regimen showed similar effects in response rate, radical resection rate and survival benefits, but with less toxicity effects.