Background Video Assisted Thoracoscopic surgical Biopsy (VATS) biopsy and transthoracic ultrasound-guided Abrams needle biopsy (TUS-GANB) are important tools in management of undiagnosed pleural effusion due to their high diagnostic yield in comparison to blind closed pleural biopsies. Methods From November 2015 to July 2017, a prospective study included a total number of 90 patients of undiagnosed pleural effusion who were randomly divided into two groups: group A (45 patients who underwent VATS biopsy), and group B (45 patients who underwent TUS-GANB). Safety and efficacy of both procedures were compared. Results Both procedures were safe with no perioperative mortality. A definitive histopathological diagnosis was obtained in 43 patients (95.6%) in group A and in 39 patients (86.7%) in group B (p = 0.266). VATS was superior to ultrasound guided biopsy in diagnosing pleural effusion due to pulmonary causes (p = 0.02). Both VATS and ultrasound guided biopsy were effective in diagnosing pleural effusion due to pleural causes (p = 0.358). Complications in group A were minor bleeding in 3 (6.7%), pain in 5 (11.1%), surgical emphysema in 1 (2.2%), prolonged air leakage in 3 (6.7%), pneumothorax in 5 (11.1%) and wound infection in 2 (4.4%). Complications in group B were minor bleeding in 1 (2.2%), pain in 2 (4.4%), surgical emphysema in 1 (2.2%), pneumothorax in 2 (4.4%) and haemoptysis in 2 (4.4%). Conclusions VATS was superior to ultrasound guided biopsy in diagnosing pleural effusion due to pulmonary causes. Both VATS and ultrasound guided biopsy were effective in diagnosing pleural effusion due to pleural causes.