Background: Image-guided pleural biopsies, both using ultrasound (US) or computed tomography (CT), are important in the diagnosis of pleural disease. However, no consensus exists regarding which biopsy needles are appropriate for specific procedures. Objectives: In this randomized, prospective study, we aimed to compare CT scan-guided pleural biopsy using an Abrams' needle (CT-ANPB) with US-assisted pleural biopsy using a cutting needle (US-CNPB) with respect to both diagnostic yield and safety. Methods: Between February 2009 and April 2013, 150 patients with exudative pleural effusion who could not be diagnosed by cytological analysis were included in the study. The patients were randomized into either the US-CNPB group or the CT-ANPB group. The two groups were compared in terms of diagnostic sensitivity and complications. Results: Of the 150 patients enrolled in this study, 45 were diagnosed with malignant mesothelioma, 46 were diagnosed with metastatic pleural disease, 18 were diagnosed with pleural tuberculosis, 34 were diagnosed with benign pleural disease, and 7 were lost to follow-up. In the US-CNPB group, the diagnostic sensitivity was 66.7%, compared with 82.4% in the CT-ANPB group; the difference between the two groups was statistically significant (p = 0.029). The sensitivity of CT-ANPB increased to 93.7% for patients with a pleural thickness ≥1 cm. The complication rates were low and acceptable. Conclusions: The first diagnostic intervention that should be preferred in patients with pleural effusion and associated pleural thickening on a CT scan is CT-ANPB. US-CNPB should be used primarily in cases for which only pleural thickening but no pleural effusion is noted.