ObjectiveTo assess the impact of patient-, lesion- and procedure-related factors on the risks of complications and final diagnosis of malignancy in PCNB of mediastinal and lung lesions. Material and MethodsWe studied a large single-center cohort of 235 consecutive patients (66.8% men; 58.5±18.0 years) with a range of thoracic benign and malignant lesions, who underwent PCNB performed along 24 months by a single experienced radiologist. Diagnostic accuracy analyses of PCNB for malignancy were performed, as well as estimations of relative risk and logistic regression models in order to assess possible associations between such factors and malignancy/complications. Results155 lesions (65.9%) were diagnosed as malignant. Overall accuracy was 91.1%, with sensitivity of 87.1%, specificity of 98.8%, positive predictive value of 99.3%, and negative predictive value of 79.8%. Pneumothorax (49/235; 20.8%) and hemorrhage (37/235; 15.7%) were the most common complications. Emphysema, smoking, older age, intrapulmonary location, deeper location, smaller size, presence of cavitations and irregular contours of the lesions, and smaller needle-pleural angles were the most consistent factors related to the occurrence of complications. Emphysema, older age, smoking, solid and deeper lesions were also significantly associated with a final diagnosis of malignancy after PCNB. ConclusionCT-guided PCNB of mediastinal and lung lesions is a safe procedure with high diagnostic accuracy for malignancy.