Background: Pleural effusion is a common challenging problem in the cardiothoracic surgery. We have different modalities for diagnosis and hence establishing the management control for the pleural effusion. Objectives: The aim of the study was to compare outcomes, in patients who underwent video-assisted thoracoscope (VATS) and patients who underwent aspiration cytology and standard thoracotomy, in diagnosis of pleural effusion. Patients and methods: This randomized clinical (interventional) study was conducted in Cardiothoracic Surgery Department, Zagazig University Hospitals. We included 48 patients with undiagnosed pleural effusion after initial and repeated biochemical and cytological analysis of the pleural fluid, they were enrolled in this study. Patients were randomly divided into three groups. Group A: Where all patients were subjected to aspiration cytology, group B: 35 cases were subjected to VATS biopsy in undiagnosed pleural effusion and group C: 13 cases were subjected to open biopsy in undiagnosed pleural effusion. Results: Pleural effusion was diagnosed by CT preoperatively and also confirmed by intra-operative findings either by VATS or by open biopsy and there were no differences between CT and intra-operative findings in presence of pleural effusion, pleural nodules and lung masses. While, there was significant difference regarding pleural thickening and mediastinal LN. 5 patients (14.3%) in VATs biopsy group failed and converted to open biopsy, 3 of them because of adhesion and 2 cases because of hemorrhage. Conclusion: Video-assisted thoracoscope is safe and minimally invasive procedure in undiagnosed pleural effusion with less operative time, blood loss, chest tube duration, intra-operative and post-operative complications and length of hospital stay compared to open biopsy.