Objective: To measure the diagnostic accuracy of percutaneous transthoracic needle lung biopsies (PTNBs) on the basis of the intention-to-diagnose principle and identify risk factors for diagnostic failure of PTNBs in a multi-institutional setting. Materials and Methods: A total of 9384 initial PTNBs performed in 9239 patients (mean patient age, 65 years [range, 20-99 years]) from January 2010 to December 2014 were included. The accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of PTNBs for diagnosis of malignancy were measured. The proportion of diagnostic failures was measured, and their risk factors were identified. Results: The overall accuracy, sensitivity, specificity, PPV, and NPV were 91.1% (95% confidence interval [CI], 90.6-91.7%), 92.5% (95% CI, 91.9-93.1%), 86.5% (95% CI, 85.0-87.9%), 99.2% (95% CI, 99.0-99.4%), and 84.3% (95% CI, 82.7-85.8%), respectively. The proportion of diagnostic failures was 8.9% (831 of 9384; 95% CI, 8.3-9.4%). The independent risk factors for diagnostic failures were lesions ≤ 1 cm in size (adjusted odds ratio [AOR], 1.86; 95% CI, 1.23-2.81), lesion size 1.1-2 cm (1.75; 1.45-2.11), subsolid lesions (1.81; 1.32-2.49), use of fine needle aspiration only (2.43; 1.80-3.28), final diagnosis of benign lesions (2.18; 1.84-2.58), and final diagnosis of lymphomas (10.66; 6.21-18.30). Use of cone-beam CT (AOR, 0.31; 95% CI, 0.13-0.75) and conventional CT-guidance (0.55; 0.32-0.94) reduced diagnostic failures. Conclusion: The accuracy of PTNB for diagnosis of malignancy was fairly high in our large-scale multi-institutional cohort. The identified risk factors for diagnostic failure may help reduce diagnostic failure and interpret the biopsy results.