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Objective: To compare the short-term and long-term efficacy of FLOT and FOLFOX in the treatment of advanced gastric cancer (GC), as well as their effects on serum tumor markers and NRP-2. Methods: 82 patients with advanced gastric cancer admitted to our hospital from March 2020 to February 2022 were selected and divided into FLOT group and FOLFOX group based on different chemotherapy methods, with 41 cases in each group. Compare the short-term and long-term efficacy, serum tumor markers and NRP-2 levels between two groups. Follow up until November 2023, record the survival status of two groups of patients and draw Kaplan-Meier survival curves. Results: The objective effective rate of FLOT group was higher than FOLFOX group (85.37% vs. 65.85%, P＜0.05) . The levels of serum carcinoembryonic antigen [ (12.77±1.85) ng/mL vs. (20.69±2.58) ng/mL], carbohydrate antigen 19-9 [ (20.46±5.20) U/m L vs. (29.41±8.04) U/m L], carbohydrate antigen 125 [ (14.90±5.61) U/m L vs. (20.72±6.23) ng/mL], and NRP-2 [ (13.01±2.11) ng/mL vs. (15.23 ±2.25) ng/mL] in the FLOT group were lower than the FOLFOX group after treatment, PFS [12.900 (95% CI:12.183～13.617) months vs. 9.600 (95% CI: 8.471～10.729) months] and OS [28.103 (95% CI: 25.209～30.996) months vs. 20.799 (95%CI: 18.482～23.115) months] were longer than the FOLFOX group (P＜0.05) . There was no difference in disease control rate and incidence of toxic side effects between the two groups (P＞0.05) . Conclusion: FLOT and FOLFOX are both effective chemotherapy regimens for mid to late stage GC, with consistent safety. However, the former has advantages in improving objective efficacy, reducing serum tumor markers and NRP-2 levels, and prolonging survival. [ABSTRACT FROM AUTHOR]