Objective To investigate the diagnostic value of tumor marker combining the probability of malignancy model in pulmonary nodules. Methods A total of 117 patients with pulmonary nodules diagnosed between January 2013 and January 2016 were retrospectively analyzed. Seventy-six cases of the patients diagnosed with cancer were selected as a lung cancer group. Forty-one cases of the patients diagnosed with benign lesions were selected as a benign group. Tumor markers were detected and the probability of malignancy were calculated. Results The positive rate of carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), neuron-specific enolase (NSE), cytokeratin marker (CYFRA21-1), and the probability of malignancy in the lung caner group were significantly higher than those of the benign group. The sensitivity, specificity, and accuracy of CEA, CA125, NSE, CYFRA21-1 combined detection were 72.37%, 73.17%, and 72.65%, respectively. Using the probability of malignancy model to calculate each pulmonary nodules, the area under ROC curve was 0.743 which was higher than 0.7; and 28.5% was selected as cut-off value based on clinical practice and ROC curve. The sensitivity, specificity, and accuracy of the probability of malignancy model were 63.16%, 78.05%, and 68.68%, respectively. The sensitivity, specificity, and accuracy of tumor marker combining the probability of malignancy model were 93.42%, 68.29%, and 92.31%, respectively. The sensitivity and accuracy of tumor marker combining the probability of malignancy model were significantly improved compared with tumor markers or the probability of malignancy model single detection (P<0.01). Conclusion The tumor marker combining the probability of malignancy model can improve the sensitivity and accuracy in diagnosis of pulmonary nodules.