VATS and transthoracic ultrasound-guided Abram`s needle biopsy are important techniques in diagnosis of pleural diseases, as they are more accurate than blind closed pleural biopsies. Methods From April 2020 to May 2022, a prospective study included 60 patients of undiagnosed pleural diseases who were randomly divided into two groups: group A (30 patients who underwent VATS biopsy), and group B (30 patients who underwent U/S guided Abram`s needle biopsy. Efficacy and safety and of both procedures were compared. Results There were no perioperative mortality and both procedures were safe. A definitive histopathological diagnosis was obtained in 30 patients (100%) in group A and in 26 patients (86.7%) in group B. Complications in group A were minor bleeding in 1 (14.3%), lung collapse in 3 (42.9%), empyema in 1 (14.3%), prolonged air leakage in 1(14.3%) and wound infection in 1 (14.3%). Complications in group B were empyema in 1 (12.5%), hemoptysis in 2 (25%), vasovagal attack in 1 (12.5%) and pneumothorax in 4 (50%). Conclusions VATS is a safe and accurate method for diagnosis of pleural lesions and pleural effusions and more sensitive than US guided Abram`s needle biopsy. VATS is an effective method in diagnosis of pleural effusion due to both pleural and pulmonary causes. The results of U/S guided Abram`s needle biopsy for pleural causes of pleural effusions is better than the results of U/S guided Abram`s needle biopsy for pulmonary causes of pleural effusions.