Objective To investigate the combined detection of serum cancer antigen(CEA)blank,carbohydrate antigen 125 (CA125)and cytokeratin 19 fragment(CYFRA21-1),neuron specific enolase(NSE)in the diagnosis of solitary pulmonary nodules. Methods 150 cases of patients with solitary pulmonary nodules diagnosed in our hospital from January 2015 to March 2017 were selected as the research subjects,including 51 lung cancer patients(Lung Cancer Group)and 51 benign lung disease patients(benign group).60 healthy people in the same period were selected as control group.The serum levels of CEA,CA125,CYFRA21-1 and NSE were detected in three groups of patients,and the clinical value of the combined detection of various indexes in the differential diagnosis of solitary pulmonary nodules was analyzed.Results The serum levels of CEA,CA125,CYFRA21-1 and NSE in patients with lung cancer were significantly higher than those in the benign and control groups(P<0.05);The sensitivity of CEA,CA125, CYFRA21-1 and NSE in differential diagnosis of malignant solitary pulmonary nodules was 32.32%,27.27%,33.33% and 40.40%,respectively.The specificity was 62.75%,52.94%,60.78%,70.59,respectively;The sensitivity of CEA + NSE+ CY-FRA21-1+CA125 in the differential diagnosis of malignant solitary pulmonary nodules was 81.82%,the specificity was 88.24%, the rate of missed diagnosis was 18.18%,the misdiagnosis rate was 11.76%,the positive predictive value was 93.10%,and the negative predictive value was 71.43%.Conclusion The combined detection of serum CEA,CA125,CYFRA21-1 and NSE has im-portant clinical value in the differential diagnosis of malignant solitary pulmonary nodules.