OBJECTIVE: Newly arising enlarged or hypermetabolic mediastinal/hilar lymph nodes (LNs) in patients with previously diagnosed extrathoracic malignancies raise suspicion of metastasis. Relatively high proportion of these LNs is due to a benign condition. We aimed to determine frequency of malignant LNs and role of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for clarification of the origin of suspicious LNs in these patients. METHODS: Consecutive patients with a known extrathoracic malignancy and suspected hilar/mediastinal LN were included in this prospective study. Computed tomography (CT) of thorax and positron emission tomography-CT of all patients were taken. LNs with short axis >1 cm at CT of thorax and SUV ≥ 2.5 were accepted suspicious for malignancy. All patients underwent EBUS-TBNA for pathological verification of LNs. Patients with benign diagnosis either underwent invasive procedures or were followed up. The results were evaluated for frequency of malignant hilar/mediastinal LNs and sensitivity, specificity, and diagnostic values of EBUS-TBNA. RESULTS: A total of 48 cases with a mean age of 57.4±11.6 were included. All cases had the diagnosis of an extrathoracic malignancy. 78 LNs were aspirated with EBUS-TBNA in 48 cases (1.62 LNs/patient). The mean short axis of aspirated LNs was 1.51±0.63. Results of EBUS-TBNA revealed malignancy in 15 cases (31.2%), tuberculosis in six cases (12.5%), sarcoidosis in four cases (8.3%), and reactive adenitis in 23 cases (48%). The sensitivity, specificity, and negative predictive value of EBUS-TBNA for malignancy were 83.3%, 100%, and 90.9%, respectively. When both benign and malignant diseases were considered, sensitivity, specificity, negative predictive value, and diagnostic accuracy of EBUS-TBNA were 89.2%, 100%, 86.9%, and 93.7%, respectively. CONCLUSIONS: The ratio of benign LNs in patients with extrathoracic malignancies is relatively high. EBUS-TBNA is a safe, minimally invasive, and effective method for clarification of intrathoracic LNs.