Background: To evaluate the clinical efficacy and adverse effect of the neoadjuvant chemotherapy with paclitaxel and S-1 in the treatment of advanced gastric cancer. Methods: The clinical data of 55 patients with advanced gastric cancer who received treatment in our department from July 2014 to July 2017 were analyzed retrospectively. Kaplan-Meier method was used for survival analysis and Cox proportional hazard model was used for multivariate prognostic analysis. Results: The R0 resection rate of neoadjuvant chemotherapy + surgery group was significantly higher than that of conventional operation group (P<0.05); the adverse reactions of neoadjuvant chemotherapy + operation group were alleviated after symptomatic treatment, without affecting the treatment effect, and gradually recovered after drug withdrawal. The Cox model showed that pathological response (P=0.002, RR=0.121, 95% CI: 0.014–0.453), clinical imaging (P=0.009, RR=0.212, 95% CI: 0.076–0.478) and TNM stage (P=0.015, RR=1.712, 95% CI: 1.021–4.123) were independent factors affecting recurrence of patients in this group. There was no significant difference in the incidence of complications between the neoadjuvant chemotherapy + operation group and the conventional operation group. Conclusion: Paclitaxel combined with S-1 is a good alternative for neoadjuvant chemotherapy of advanced gastric cancer with less adverse effects.