Computed tomography-guided percutaneous transthoracic needle biopsy (PTNB) is used for identifying paramediastinal lung lesions that cannot be diagnosed by bronchoscopy, but the diagnostic performance and complication rate are unreported.This retrospective study was approved by the institutional review board committee. A total of 1484 patients who underwent PTNB between April 2012 and April 2015 were enrolled. The cohort was divided into a paramediastinal (n = 195) and a nonparamediastinal group (n = 1289) based on lesion location. Diagnostic yield for malignancy and complication rates were analyzed in both groups. Univariate and multivariate logistic regression analysis was used to determine independent risk factors for hemoptysis complication in the paramediastinal group.Percutaneous transthoracic needle biopsy showed 95.6% (109/114) sensitivity and 100% (77/77) specificity for the diagnosis of lesions in the paramediastinal group, with similar accuracy (95.4%, 186/195) to that in the nonparamediastinal group (94.7%, 1221/1289; P = 0.699). Compared with PTNB for nonparamediastinal lesions, PTNB for paramediastinal lesions demonstrated a comparable pneumothorax rate (8.21% vs 8.69%; P = 0.823) and hemothorax rate (2.56% vs 1.47%; P = 0.261), and a higher hemoptysis rate (28.2% vs 19.4%; P = 0.005). Among 6 defined paramediastinal regions, the overall complication rate was the highest in the posterior region (42.4%) and the lowest in the paraventricular region (13.6%). Multivariate analysis revealed that lesion size of 2 to 3 cm (odds ratio [OR] 3.22), intrapulmonary length of needle path >2 cm (OR 8.85), and proximal to pulmonary artery (OR 10.33) were independent risk factors for hemoptysis in the paramediastinal group.Computed tomography-guided PTNB can diagnose paramediastinal lesions with high yield and acceptable complication rates. Given higher rate of hemoptysis in PTNB for paramediastinal lesions, more attention should be paid in cases with high risks.