Abstract: Objective To explore the clinical value of cytokeratin 19 fragment (CYFRA21-1), matrix metalloproteinase 9 (MMP-9) and thyroid transcription factor -1 (TTF-1) in identifying benign and malignant lung tumors. Methods Twenty seven cases of malignant lung tumors, 45 cases of benign lung tumors, and 30 healthy subjects who were admitted to Lishui People's Hospital of Zhejiang Province from March 2016 to May 2018 were selected and assigned into malignant tumor groups, benign tumors group and control group. The levels of CYFRA21-1 were detected by electrochemiluminescence and the levels of TTF-1 and MMP-9 were detected by enzyme-linked immunosorbent assay. Results The serum levels of CYFRA21-1, MMP-9 and TTF-1 in the malignant tumor group were significantly higher than those in the benign tumor group and the healthy control group, and the difference was statistically significant (all P<0.05). Logistic regression analysis showed that there was no correlation between CYFRA21-1, MMP-9 and TTF-1 and benign lung tumors (all P>0.01), which was correlated with malignant lung tumors (all P<0.01). ROC curve analysis showed that the AUC of serum CYFRA21-1 in differentiating benign and malignant lung tumors was significantly higher than that of MMP-9 and TTF-1, and the difference was statistically significant (all P<0.05), and there was no significant difference between MMP-9 and TTF-1 (P>0.05). The sensitivity and specificity of serum CYFRA21-1 were 67.8%, 93.1%, of MMP-9 were 42.1% and 87.2%, and of TTF-1 were 44.3% and 95.7%, respectively. Conclusion The serum levels of CYFRA21-1, MMP-9 and TTF-1 have certain potential value in differential diagnosis of benign and malignant lung tumors, among which CYFRA21-1 is the highest.