Objective: To investigate postoperative complications of patients undergoing neoadjuvant therapy followed by radical gastrectomy, and to analyze their influence on the prognosis. Methods: A retrospective case-control study was used. Case inclusion criteria: (1) gastric adenocarcinoma confirmed by histopathology; (2) preoperative imaging examination showed no distant metastasis or peritoneal dissemination; (3) undergoing radical gastrectomy and D2 lymph node dissection after neoadjuvant therapy; (4) complete clinicopathological and follow-up data. According to the above criteria, clinical data of 490 gastric cancer patients who underwent radical gastrectomy in the Cancer Hospital of Chinese Academy of Medical Sciences, Peking Union Medical College from January 2008 to December 2018 were retrospectively collected, including 358 males and 132 females with mean age of (55.0±10.6) years. Neoadjuvant chemotherapy regimens included SOX (S-1+ oxaliplatin, n=151), XELOX (capecitabine+oxaliplatin, n=155), FLOT (docetaxel+oxaliplatin+fluorouracil, n=66), and DOS (docetaxel+ oxaliplatin+S-1, n=68). Preoperative concurrent chemoradiotherapy was performed in 100 patients. SOX regimen was used for 2-4 cycles as induction chemotherapy plus concurrent chemoradiotherapy (3D IMRT+S-1). Postoperative complications were defined as surgery-related complications, mainly including hemorrhage, anastomotic leakage, obstruction, anastomotic stenosis, pulmonary infection, abdominal infection, etc. Postoperative complications were graded according to Clavien-Dindo classification. Log-rank test and Cox regression model were used for univanriate multivariate prognostic analysis, respectively. Results: A total of 101 complications ocaured after operation in 87 (17.8%) patients, including 29 cases of major complications (Clavien-Dindo III to V), and 58 cases of minor complications (Clavien-Dindo I to II). Multivariate analysis showed that age > 65 years (HR=3.077, 95% CI: 1.827-5.184, P<0.001) and total gastrectomy (HR=1.735, 95% CI: 1.069-2.814, P=0.026) were independent risk factors for postoperative complications in patients with gastric cancer undergoing neoadjuvant therapy and radical gastrectomy (both P<0.05). The follow-up period was 0.7 to 131.8 months (median 21.5 months), and the 5-year overall survival rate was 47.4%. The 5-year overall survival rates of the complication group (87 cases) and the non-complication group (403 cases) were 33.2% and 50.9%, respectively (P=0.001). Multivariate analysis showed that age (HR=1.906, 95% CI: 1.248-2.913, P=0.003), ypTNM II to III stage (II stage: HR=5.853, 95% CI: 1.778-19.260, P=0.004; III stage: HR=10.800, 95% CI: 3.411-34.189, P<0.001), surgery time>3.5 h (HR=1.492, 95% CI: 1.095-2.033, P=0.011), total gastrectomy (HR=1.657, 95% CI: 1.216-2.257, P=0.001) and postoperative complications (HR=1.614, 95% CI: 1.125-2.315, P=0.009) were independent risk factors for prognosis, and postoperative adjuvant therapy (HR=0.578, 95% CI: 0.421-0.794, P=0.001) was an independent protective factor for prognosis. Conclusions: The occurrence of postoperative complications in gastric cancer patients undergoing neoadjuvant therapy is closely related to the age of the patients and the range of surgical resection. It is beneficial to improve the prognosis for these patients by paying more attention to the prevention of postoperative complications and the reinforcement of postoperative adjuvant therapy.