Abstract: Objective To evaluate the clinical efficacy and safety of neoadjuvant chemotherapy with FOLFOX4 (5-fluomumcil/leucovorin combined with oxaliplatin) regimen for advanced gastric cancer. Methods Fifty-eight patients with advanced gastric cancer were enrolled, 23 cases in the experimental group (FOLFOX4 regimen neoadjuvant chemotherapy) and 35 cases in control group. The clinical response rate, R0 resection rate, survival data and adverse events were compared between two groups. Results The two groups were well-matched in baseline clinical and pathological data. The clinical response rate was 43.5% in the experimental group. The number of lymph node metastases in the experimental group 3 (0-14) was significantly less than that in control group 6 (0-27) (P=0.04). There was no significant differences in R0 resection rate (82.6% vs. 82.0%) or lymph node dissection number16 (0-49) vs.13 (3-40) between two groups (P>0.05). The median overall survival (OS) were 29.0 months (95%CI: 25.3-32.7 months) in the experimental group and 22.0 months (95%CI: 18.2-25.8 months) in control group (P=0.013). The 3-year OS rate in the experimental group (73.9%) was significantly higher than that in control group (40.0%). Cox regression multivariate analysis identified neoadjuvant chemotherapy and tumor distant metastasis as independent prognostic factors. Adverse events were mainly hematological and gastrointestinal and were well-tolerated in most cases (P>0.05). Conclusion The FOLFOX4 regimen as neoadjuvant chemotherapy could reduce lymph node metastasis and improve survival without increasing adverse events in patients with advanced gastric cancer.