Objective To evaluate the clinical efficacy of comprehensive treatment for synchronous primary advanced gastric and esophageal cancer by propensity score matching (PSM). Methods A total of 2 551 patients with advanced gastric cancer admitted to Jiangsu Province Hospital of Chinese Medicine from January 2013 to December 2022 were retrospectively analyzed. Among them, 45 patients with synchronous primary esophageal cancer were distributed to the observation group, and 2 506 patients without esophageal cancer were distributed to the control group. Through the PSM method, the control group was matched with the observation group and the equilibrium samples of covariates between two groups were obtained. The overall survival(OS) between the two groups were compared. Results Both observation and control group contained 45 patients in this study. According to the treatment regimen, the patients in the observation group was divided into radical resection treatment subgroup (n=22) and chemoradiotherapy (CRT) subgroup (n=23). In the radical resection subgroup, 4 patients underwent the simultaneous surgical resection of gastric and esophageal tumors through proximal gastrectomy with the Ivor Lewis operation. Eighteen patients underwent endoscopic submucosal dissection(ESD) of their esophageal tumors and gastric cancer radical resection. Radical resection of gastric cancer combined with preoperative chemoradiotherapy of esophageal cancer was performed in the CRT subgroup. Survival analysis showed that OS in the observation group was significantly shorter than that in the control group (P=0.042) and there was no significant difference in OS between the radical resection subgroup and the control group (P=0.799). The 1 -, 3 -, and 5-year survival rates of the patients in the CRT subgroup were significantly lower than those of the control group (P=0.003). While the 1 -, 3 -, and 5-year survival rates of the patients in the radical resection subgroup were not statistically significant, compared to those of the CRT subgroup (P=0.071).Conclusions Multidisciplinary and comprehensive treatment can significantly improve the prognosis of patients with synchronous primary advanced gastric and esophageal cancer. Radical resection of gastric cancer combined with ESD of esophageal cancer is an optional treatment for patients with gastric cancer complicated with early esophageal cancer. Radical resection of gastric cancer combined with CRT of esophageal cancer can improve the prognosis of patients with advanced gastric cancer complicated with unresectable esophageal cancer.