Managing pleural infection can be challenging due to the significant morbidity and mortality of this healthcare problem. Identifying the causative organism poses a significant difficulty, as traditional cultures have low sensitivity. To address this issue, this study aimed to investigate the role of pleural tissue culture in improving the microbiological yield for pleural infections. Methods: This study was conducted at the Chest Department of Kasr Al-Ainy Hospital, Cairo University, and involved 30 patients diagnosed with pleural infection. Of these, 17 patients underwent ultrasound-guided true-cut needle biopsies, while 13 underwent thoracoscopic pleural biopsies. Tissue samples, pleural fluid, and blood were collected from all patients for culture and analysis. Results: The mean age of patients was 39 ± 15 years, with 90% male. The incidence of intravenous drug addiction was 23%, and 73% had poor dental hygiene. Of the patients, 20% had diabetes. The pleural fluid culture was positive in 17% of patients (5 out of 30), and the blood culture was positive in 16.7% (2 out of 30). Most pleural tissue cultures were negative, with only 3.3% being positive. Conclusion: Whether ultrasound-guided or thoracoscopic, tissue culture does not increase the microbiological yield compared to conventional pleural fluid culture. Therefore, further research is necessary to determine the potential benefits of medical thoracoscopy in diagnosing and managing pleural infections.