Objective: To explore soluble growth stimulation expressed gene 2 protein (ST2), carcinoembryonic antigen（CEA） and cytokeratin fragment 21-1 (CYFRA211) in diagnosing early non-small cell lung cancer (NSCLC). Methods: From January to August 2023, 91 patients with early NSCLC (TNM stage Ⅰ) and 21 patients with middle and advanced NSCLC [TNM stage Ⅱ (16 cases) and Ⅲ (5 cases)] admitted to Ruijin Hospital were collected, and 50 patients with benign lung lesions(BL) and 50 healthy people(HC) were served as controls. Plasma ST2 levels were detected by fluorescence immunochromatography, and serum CEA and CYFRA211 levels were detected by chemiluminescence. The differences between groups were compared, and the diagnostic value of index alone or in combination for NSCLC was analyzed. Results: ST2 level in the early NSCLC group was higher than that in the BL and HC group （P<0.001), and ST2 level in BL group was higher than HC group (P<0.001). The CEA level in the early NSCLC group were higher than that in the HC group (P<0.05), BL group was higher than HC group (P<0.05). The CYFRA211 level in the early NSCLC group was higher than that in the HC group (P<0.05). When the cutoff values of ST2, CEA and CYFRA211 were set as 25.0 ng/L, 1.8 ng/mL and 2.0 ng/mL, areas under receiver operator characteristic (ROC) curve for diagnosing early NSCLC were 0.957, 0.660 and 0.570, respectively. The sensitivity of ST2,CEA and CYFRA211 for diagnosing early NSCLC were 89.0%, 46.2% and, 17.6%,and specificity were 98.0%, 80.0%, 96.0%, respectively. The area under the curve of the combined detection were 0.973, with a sensitivity of 92.3% and the specificity of 98.0%,which were higher than that of any index. In terms of clinicopathological features, plasma ST2 level was higher in NSCLC patients with larger tumors than with smaller tumors（P<0.05）. There were statistical differences in CEA levels among groups with different degrees of tumor differentiation, between groups with and without regional lymph node metastasis, groups with and without airway spread, groups with and without pleural invasion, and groups with TMN stage Ⅰ and TMN Ⅱ/Ⅲ/Ⅳ（P<0.05）. CYFRA211 levels were significantly different between diffe-rent sex groups, age groups and lung cancer types (P<0.05). Conclusions: Compared with CEA and CYFRA211, ST2 alone is more advantageous in distinguishing early NSCLC patients from patients with benign lung lesions and healthy controls. However, combined detection of the three tests has higher diagnostic value and is recommended to assist the diagnosis of early NSCLC.