Objective To explore the efficacy of a novel detection technique of circulating tumor cells (CTCs) to identify benign and malignant lung nodules. Methods Nanomagnetic CTC detection based on polypeptide with epithelial cell adhesion molecule (EpCAM)-specific recognition was performed on enrolled patients with pulmonary nodules. There were 73 patients including 48 patients with malignant lesions as a malignant group and 25 patients with benign lesion as a benign group. There were 13 males and 35 females at age of 57.0±11.9 years in the malignant group and 11 males and 14 females at age of 53.1±13.2 years in the benign group. e calculated the differential diagnostic efficacy of CTC count, and conducted subgroup analysis according to the consolidation-tumor ratio, while compared with PET/CT on the efficacy. Results CTC count of the malignant group was significantly higher than that of the benign group (0.50/ml vs. 0.00/ml, P<0.05). Subgroup analysis according to consolidation tumor ratio (CTR) revealed that the difference was statistically significant in pure ground glass (pGGO) nodules 1.00/mlvs. 0.00/ml, P<0.05), but not in part-solid or pure solid nodules. For pGGO nodules, the area under the receiver operating characteristic (ROC) curve of CTC count was 0.833, which was significantly higher than that of maximum of standardized uptake value (SUVmax) (P<0.001). Its sensitivity and specificity was 80.0% and 83.3%, respectively. Conclusion The peptide-based nanomagnetic CTC detection system can differentiate malignant tumor and benign lesions in pulmonary nodules presented as pGGO. It is of great clinical potential as a noninvasive, nonradiating method to identify malignancies in pulmonary nodules.