Background: Trastuzumab (Herceptin) in combination with capecitabine and cisplatin has been the standard first-line chemotherapy in patients with HER2-positive advanced gastric cancer (AGC). Oxaliplatin is generally less toxic and more convenient than cisplatin, and currently replacing cisplatin for the treatment of AGC. This study aims to investigate the efficacy and safety of trastuzumab in combination with capecitabine and oxaliplatin (HER-XELOX) in HER2-positive AGC. Methods: With Simon’s minimax two stage design (P₀[response rate of historic control]=0.4, P₁=0.55, two-sided alpha=0.1, beta=0.2, and 10% drop-out rate), a total of 55 patients with AGC positive for HER2 defined as either HER2 immunohistochemistry (IHC) 3+ or IHC 2+and FISH+ were enrolled from Aug 2011 to Feb 2013. HER-XELOX regimen consisted of trastuzumab 8 mg/kg i.v. on day 1 in cycle 1 and then 6 mg/kg in subsequent cycles, capectabine 2000 mg/m²/day p.o. on days 1-14, and oxaliplatin 130 mg/m²i.v. on day 1, every 3 weeks. HER-XELOX was administered as a first-line chemotherapy until disease progression, unacceptable toxicity, or consent withdrawal. Results: Among the 55 patients, 37 (66%) patients were male. Median age was 57 years (range, 29-74). ECOG performance status was 0-1 in 51 (93%) patients. Fifty three (96.4%) patients had metastatic disease, and 2 (3.6%) had locally advanced unresectable disease. With complete response in 2 patients and partial response in 35 patients, confirmed overall response rate was 67.3% (95% CI, 54-80%). With a median follow-up of 13.8 months (range, 6.1-23.9) in surviving patients, median progression-free survival was 9.8 months (95% CI, 7.0-12.6). Median overall survival was 21.0 months (95% CI, 6.4-35.7). Common grade 3 or 4 toxicities with frequency > 10% included neutropenia (18.2%), anemia (10.9%), and neuropathy (10.9%). There was no febrile neutropenia. One patient died of treatment-related diarrhea and sepsis. Conclusions: HER-XELOX regimen is well tolerated and highly effective in patients with HER2-positive AGC. Clinical trial information: NCT01396707.