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Background: Endobronchial ultrasound-guided transbronchial fine-needle aspiration (EBUS-FNA) has gained acceptance as the diagnostic procedure of choice with which to sample hilar and mediastinal lymph nodes (LNs) for diagnosing and staging patients with lung cancer. Studies have shown that EBUS has a high positive predictive value; however, its negative predictive value (NPV) varies significantly. The aim of the current study was to evaluate the clinical outcome surrounding negative and nondiagnostic EBUS-FNA of mediastinal LNs., Methods: A retrospective chart review of cases of EBUS-FNA performed between 2008 and the middle of 2011 was conducted. Mediastinal LNs with cytologic diagnoses of negative for malignant cells and unsatisfactory were selected for the study. Each LN was followed for up to 1 year with imaging or biopsy/surgical resection. A true-negative result was defined as a LN that did not enlarge on repeat imaging or was negative for malignancy on repeat biopsy or surgery during the follow-up period., Results: Among 1418 LNs sampled, 479 from 228 patients met the search criteria, including 394 LN (82.3%) with the cytologic diagnosis of negative for malignant cells and 85 (17.8%) with a diagnosis of unsatisfactory. A total of 104 patients (45.6%) were followed with imaging, and 124 patients (54.3%) underwent repeat biopsy/surgery. A total of 445 LNs met the definition of a true-negative finding, resulting in an overall NPV of 92.9% (95% confidence interval [95% CI], 90.6%-95.2%). The NPVs of a negative and unsatisfactory diagnosis were 93.9% (95% CI, 91.6%-96.3%) and 88.2% (95% CI, 81.4%-95.1%), respectively., Conclusions: The vast majority of LNs with a cytologic diagnosis of negative and unsatisfactory were likely to be true-negative findings. In these patients, a more conservative approach to follow-up may be appropriate., (© 2014 American Cancer Society.)