Objective:To evaluate the diagnostic value of peripheral blood circulating tumor cells (CTC) and serum pepsinogen (PG) I for early gastric cancer (EGC).Methods:A case-control study was conducted utilizing the clinical data of 102 patients with gastric mucosal lesions treated at Shaanxi Provincial Cancer Hospital between January 2021 and December 2022. Based on the diagnostic outcomes, these patients were categorized into a benign lesion group ( n = 54) and an EGC group ( n = 48). Patient demographics were compared between the two groups. Additionally, CTC and PG I-positive rates were compared between the two groups. The diagnostic effectiveness of CTC and serum PG I alone in identifying EGC was evaluated. Independent factors influencing EGC diagnosis were analyzed, and the predictive diagnostic value of CTC and serum PG I for EGC was calculated. Results:There was no statistically significant difference in gender and age between the two groups (both P > 0.05). The positivity rates of CTC and serum PG I in the EGC group were 79.17% (38/48) and 70.83% (34/48), respectively, which were significantly higher than those in the benign lesion group [14.81% (8/54), 20.37% (11/54), χ2 = 42.50, 26.25, both P < 0.001]. The diagnostic sensitivity, specificity, positive predictive value, and negative predictive value of CTC and serum PG I alone did not show statistically significant differences in diagnosing EGC (all P > 0.05). Multivariate logistic regression analysis revealed that CTC and serum PG I positivity were independent risk factors for EGC ( OR = 20.20, 8.57, both P < 0.05). Using CTC, serum PG I, and the P-value prediction probability derived from the logistic regression model, the Jordan indices for predicting the diagnosis of EGC were 0.643, 0.504, and 0.633, respectively. Conclusion:The combination of CTC and PG I is highly significant for the diagnosis of EGC, and two detection methods are crucial for accurate risk assessment of EGC.