BACKGROUND In cases of pleural effusion, tissue samples can be obtained through Abrams needle pleural biopsy (ANPB), thoracoscopy, or cutting-needle pleural biopsy under the guidance of CT scan (CT-CNPB) for histopathologic analysis. This study aimed to compare the diagnostic efficiency and reliability of ANPB under CT scan guidance (CT-ANPB) with that of medical thoracoscopy in patients with pleural effusion. METHODS Between January 2006 and January 2008, 124 patients with exudative pleural effusion that could not be diagnosed by cytologic analysis were included in the study. All patients were randomized after the CT scan was performed. Patients either underwent CT-ANPB or thoracoscopy. The two groups were compared in terms of diagnostic sensitivity and complications associated with the methods used. RESULTS Of the 124 patients, malignant mesothelioma was diagnosed in 33, metastatic pleural disease in 47, benign pleural disease in 42, and two were of indeterminate origin. In the CT-ANPB group, the diagnostic sensitivity was 87.5%, as compared with 94.1% in the thoracoscopy group; the difference was not statistically significant (P = .252). No difference was identified between the sensitivities of the two methods based on the cause, the CT scan findings, and the degree of pleural thickening. Complication rates were low and acceptable. CONCLUSIONS We recommend the use of CT-ANPB as the primary method of diagnosis in patients with pleural thickening or lesions observed by CT scan. In patients with only pleural fluid appearance on CT scan and in those who may have benign pleural pathologies other than TB, the primary method of diagnosis should be medical thoracoscopy. BACKGROUND clinicaltrials.gov; Identifier: NCT00720954.