Background and Objective. EBUS-TBNA has revolutionized the diagnostic approach to thoracic diseases from a surgical to minimally invasive procedure. In non small-cell lung cancer (NCSLC) patients, EBUS-TBNA is able to dictate the consecutive therapy both for early and advanced stages, providing pathological diagnosis, mediastinal staging, and even adequate specimens for molecular analysis. This study reports on the ability of EBUS-TBNA to make different diagnoses and dictates the consecutive therapy in a large cohort of patients presenting different thoracic diseases. Methods. All procedures performed from January 2012 to September 2016 were reviewed. Five groups of patients were created according to the main indications for the procedure. Group 1: lung cancer staging; Group 2: pathological diagnosis in advanced stage lung cancer; Group 3: lymphadenopathy in previous malignancies; Group 4: pulmonary lesions; Group 5: unknown origin lymphadenopathy. In each group, the diagnostic yield of the procedure was analysed. Non malignant diagnosis at EBUS-TBNA was confirmed by a surgical procedure or clinical and radiological follow-up. Results. 1891 patients were included in the analysis. Sensitivity, negative predictive value, and diagnostic accuracy in each group were 90.7%, 79.4%, and 93.1% in Group 1; 98.5%, 50%, and 98.5% in Group 2; 92.4%, 85.1%, and 94.7% in Group 3; 90.9%, 51.0%, and 91.7% in Group 4; and 25%, 83.3%, and 84.2% in Group 5. Overall sensitivity, negative predictive value, and accuracy were 91.7%, 78.5%, and 93.6%, respectively. Conclusions. EBUS-TBNA is the best approach for invasive mediastinal investigation, confirming its strategic role and high accuracy in thoracic oncology.