Objective To investigate the clinical significance of circulating tumor cells (CTC) in gastric cancer patients treated with surgery and to assess its prognostic value for gastric cancer patients. Methods A case-control study was conducted to retrospectively collect the clinicopathological data of gastric cancer patients who underwent radical gastric cancer surgery at the Department of General Surgery, First Medical Center of the Chinese People’s Liberation Army General Hospital between April 2015 and July 2017, and who underwent postoperative CTC examination. The optimal cut-off value was determined by drawing a receiver operating characteristic (ROC) curve based on CTC levels and patient survival, and patients were divided into CTC-positive and negative groups based on this cut-off value to investigate the differences in clinicopathological characteristics between the two groups. Patients with gastric cancer were followed up and survival was recorded until September 30, 2020. The Kaplan-Meier method was used to calculate the 3-year overall survival rate and plot survival curves, and Cox regression models were used to conduct univariate and multifactorial analyses of patient prognostic factors to explore the factors affecting the survival of patients after gastric cancer surgery. Results A total of 242 patients with gastric cancer were included in this study. The results of ROC curve analysis showed that the most statistically significant CTC cut-off value for patient survival difference was 1, which meant that patients were considered positive when CTC was detected in their blood. Forty-nine cases (20.2%) in the CTC positive group had a positive cell count of 1 to 32 cells/7.5 mL, with a median of 2 cells/ 7.5 mL, and 193 cases (79.8%) in the negative group. Comparison of baseline data between the two groups showed that there were no statistically significant differences in patients’ age, gender, tumor site, surgical method, type of resection, anastomosis, tumor diameter, lymph node metastasis and nerve invasion (all P>0.05), and statistically significant differences in body mass index, choroidal carcinoma embolus, degree of tumor differentiation, tumor pathological type, and tumor TNM stage (all P<0.05). The median follow-up time after surgery for 242 gastric cancer patients was 42 (3–67) months, and the 3-year survival rates were 49.0% and 72.5% in the CTC-positive and -negative groups, respectively, with statistically significant difference (χ2=17.129, P<0.001). The results of univariate analysis showed that age, tumor site, type of resection, anastomosis, tumor diameter, lymph node metastasis, choroidal carcinoma embolism, nerve invasion, degree of tumor differentiation, tumor TNM stage, and whether CTC was positive or not were the important factors affecting the overall survival rate of gastric cancer patients (all P<0.05). The results of multivariate analysis showed that age >60 years old [HR=3.009, 95%CI(1.807, 5.010), P<0.001], tumor TNM Ⅲ–Ⅳ stage [HR=3.082, 95%CI (1.504, 6.317), P=0.002] and positive CTC [HR=2.488, 95%CI (1.475, 4.197), P=0.001] were independent risk factors affecting the survival of gastric cancer patients. Conclusion CTC is correlated with the prognosis of gastric cancer patients and can be used as a potential indicator to determine the prognosis of gastric cancer patients.