Abstract: Objective: To assess the value of multiple imaging signs on high-resolution CT in the differential diagnosis between benign and malignant solitary pulmonary nodules (SPN). Methods: 102 cases of SPN with surgery or pathologically confirmed from April 2016 to April 2018 were retrospectively analyses. The data's of multiple image signs on high-resolution CT for diagnosing benign and malignant lesions were collected, and the diagnosis accuracy of combined and single signs were compared. Results: The incidence of calcification in malignant lesions was 4.26%, which was lower than that of benign lesions. The incidences of lobulation signs, vascular bundle signs and burrs signs were 63.83%, 40.43% and 70.21% respectively in malignant lesions, all of these were higher than those of benign lesions. All of the differences mentioned above were statistically significant (P<0.05). No significant differences were shown in the incidence of satellite foci, vacuolar sign and pleural depression between benign and malignant lesions (P>0.05). The positive predictive value of combined signs of vascular bundle signs, burr signs and lobulation signs was significantly higher than that of single sign (P<0.05). Conclusion: High-resolution CT signs are of high value in the differential diagnosis of benign and malignant SPN, and combined multiple CT signs is higher accuracy than single CT sign.