Mediastinitis is a rare complication of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). Recent reports of infectious complications following EBUS-TBNA involved oropharyngeal bacteria. Here, we report 2 unusual cases of post-EBUS-TBNA mediastinitis involving Streptococcus pneumoniae and Pseudomonas aeruginosa, which were likely the result of direct inoculation of the organisms at the time of transbronchial needle aspiration. The first case was successfully treated with computed tomography-guided drainage and antibiotics, whereas the second case had >50% distal tracheal obstruction and near total occlusion of the left main stem bronchus, requiring rigid bronchoscopy, stent placement, debulking, and antibiotics. Review of literature suggests that the isolated pathogens are rare in this setting and are most likely not related to oropharyngeal contamination during bronchoscope insertion. Active bronchitis should be considered an additional risk factor for EBUS-TBNA-induced mediastinitis. We suggest possible methods to decrease the risk of this serious postprocedure complication. It is important to be vigilant about the possibility of mediastinitis in patients that undergo EBUS-TBNA. Fever and respiratory symptoms should lower the threshold for ordering a computed tomography chest for early detection and management. Our patients did not require thoracic surgery for the management of the mediastinitis.