Objective To explore the diagnostic value and safety of CT-guided percutaneous lung biopsy (CT-PLB) for pulmonary nodules. Methods A total of 438 patients with pulmonary nodules underwent CT-PLB for further diagnosis. Results The CT-PLB was performed successfully in all 438 patients. The positive biopsy rate at the first puncture was 94.9%, and 100.0% at the second puncture. The pathology results revealed 379 (86.5%) cases of malignant lesions, 37 cases of benign lesions, and 22 cases with uncertainty. The sensitivity, specificity and accuracy of CT-PLB were 97.9% (376/384), 94.4% (51/54), and 97.4% (427/438), respectively. The first puncture induced complications included pneumothorax in 33 (7.5%) cases, blood in phlegm in 62 (14.2%) cases, pleural reaction in 7 (1.6%) cases, and bleeding at the site of puncture in 6 (1.4%) cases. There was no occurrence of neoplasm needle track implantation. The second puncture induced complications included pneumothorax in 7 (46.6%) cases and blood in phlegm in 11 (73.3%) cases. The incidences of pneumothorax and blood in phlegm were significantly higher in the patients with chronic obstructive pulmonary disease (COPD), with pulmonary lesion size＜3 cm, or with penetration depth ≥5 cm (P＜0.05). Conclusions CT-PLB is a safe method with a relatively small trauma and has good diagnostic value for pulmonary nodules. The incidence of complications increases in patients with smaller pulmonary lesions, deeper puncture, or COPD.