Background: Mediastinal masses are an uncommon abnormalities found in clinical practice and tissue diagnosis of these masses are very important for correct therapeutic decision. Objective: Comparing the usefulness of invasive procedure for histological diagnosis of a mediastinal masses. Patients and methods: This was a prospective study of 50 patients who were admitted in Cardiothoracic Surgery Department, Al-Zahraa University Hospital, Al-Azhar University during the period between December, 2011 and April, 2014. They were diagnosed by plain X-ray and computed tomography (CT) for site detection of mediastinal masses. After taken an appropriate consent from them, they underwent fine needle aspiration (FNA) guided by CT, trans bronchial needle aspiration (TBNA), mediastinoscopy, sternotomy and thoracotomy. Cytology smears and histological sections were evaluated in all patients. Results: Among 50 patients, 49 were Egyptian and one patient from Ghana; 29 males and 21 females with the mean age of 43.06±3.44 years. 50% of masses were identified in patients with age more than 40 years of life. 20, 23 and 7 patients have lesion at the anterior, middle posterior parts of the mediastinum respectively. The overall sensitivity for FNA guided by CT, TBNA,  mediastinoscope,  sternotomy and thoracotomy were 80.0%, 66.7%, 95.0%, 100% and 100% respectively. Sarcoidosis and metastatic carcinoma were the most common entity (16%) followed by tubercular granuloma and nonHodgkin's lymphoma (NHL) (14.0%). Only one patient (2%) developed moderate pneumothorax with no mortality. Conclusion: FNA guided by CT and TBNA are safe, minimally invasive and cost-effective procedures, which can provide a precise diagnosis in the mediastinal masses inspite of lower sensitivity other than invasive surgical approaches like mediastinoscope, sternotomy and thoracotomy.