Staging guidelines for lung cancer recommend endobronchial ultrasound (EBUS) and systematic biopsy of at least three mediastinal lymph node (LN) stations for accurate staging. A four-point ultrasonographic score (Canada Lymph Node Score [CLNS]) was developed to determine the probability of malignancy in each LN. A LN with a CLNS of 2 is considered low probability for malignancy. We hypothesized that, in patients with cN0 non-small cell lung cancer, LNs with CLNS of 2 may not require routine biopsy because they represent true node-negative disease.Do LNs considered triple normal on CT scanning, PET scanning, and CLNS evaluation require routine biopsy?LNs were evaluated for ultrasonographic features at the time of EBUS and the CLNS was applied. Triple-normal LNs were defined as cN0 on CT scanning (short axis, 1 cm), PET scanning (no hypermetabolic activity), and EBUS (CLNS, 2). Specificity and negative predictive value (NPV) were calculated against the gold standard pathologic diagnosis from surgically excised specimens.In total, 143 LNs from 57 cN0 patients were assessed. Triple-normal LNs showed a specificity and NPV of 60% (95% CI, 51.2%-68.3%) and 93.1% (95% CI, 85.6%-97.4%), respectively. After pathologic assessment, only 5.6% (n = 8/143) of triple-normal nodes were proven to be malignant.At the time of staging for lung cancer, combining CT scanning, PET scanning, and CLNS criteria can identify triple-normal LNs that have a high NPV for malignancy. This raises the question of whether triple-normal LNs require routine sampling during EBUS and transbronchial needle aspiration. A prospective trial is required to confirm these findings.