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Objective To investigate the efficacy and safety of computed tomography-guided transthoracic needle biopsy( CT-guided TNB), and to explore the strategies for more diagnostic yield and lower complications. Methods Totally120 cases who underwent CT-guided TNB were enrolled. The CT images were analyzed carefully and the optimal approach was selected. The lung biopsy was performed with Argon coaxial trocar and biospsy needle. Artificial pneumothorax was established if necessary. In some cases, the combination of the CT and PET/CT-guided TNB was applied. The puncture success rate, diagnostic yield and the complications were assessed. The key points of procedure were studied. Results In120 patients, 130 times of procedure were performed. 1, 2 and 3 times of procedure were performed respectively on 111, 8, and 1 patients. Totally 127 times of procedure were successful. The procedure success rate was 97. 69%( 127/130).In 120 patients, 119 patients achieved accurate diagnosis, which included 82 cases of lung cancer, 9 cases of tuberculosis, 9 cases of non-specific pneumonia, 6 cases of organizing pneumonia, 4 cases of fungal pneumonia, 4 cases of vasculitis, 2 cases of sarcoidosis, 2 cases of lymphoma and 1 case of eosinophilic pneumonia, with the diagnostic rate of 99. 17%( 119/120). Twelve nodes with diameters < 1 cm were punctured successfully, with the minimum diameter of 0. 7 cm. One case with discreted lesion was punctured successfully with artificial pneumothorax which concentrated the lesion; 2 cases of lesions adjacent to heart and large vessel were punctured successfully with artificial pneumothorax which separated the lesions from heart or large vessel; 7 cases with initial pathologic finding of inflammation by CT-guided TNB and poor anti-inflammation were proved finally to be lung cancer by combining with PET-CT guided pre-procedure. Twenty-four of 120 cases had complications. The incidence of complication was 20%, which included 11 cases of pneumothorax, 8 cases of hemoptysis, 2 cases of pleural infection, and 2 cases of hemothorax. No fatal complications occurred. Conclusions CT-guided TNB is an accurate, effective and safe measure. The key points of procedure include analyzing CT images carefully to select the optimal approach away from vessels and bullae of lung pre-procedure, using Argon coaxial trocar and biospsy needle, applying artificial pneumothorax for the lesions adjacent to heart and large vessels and discreted lesion, and combining with PET-CT guided positioning for the mixture lesions with malignant and inflammation. [ABSTRACT FROM AUTHOR]