Background: Apoptosis plays a role in the development of pleural effusion. Caspase-cleaved cytokeratin 18, a marker for epithelial cell apoptosis, was evaluated in pleural effusion. Methods: A total of 79 patients with pleural effusion were enrolled. The underlying causes were lung cancer (n=24), parapneumonic effusion (n=15), tuberculous effusion (n=28), and transudates (n=12). The levels of M30, an epitope of caspase-cleaved cytokeratin 18, were measured in blood and pleural fluids using enzyme-linked immunosorbent assay along with routine cellular and biochemical parameters. The expression of M30 was evaluated in the pleural tissues using immunohistochemistry for M30. Results: The M30 levels in pleural fluid were significantly higher in patients with tuberculosis ($2,632.1{pm}1,467.3U/mL$) than in patients with lung cancer ($956.5{pm}618.5U/mL$), parapneumonic effusion ($689.9{pm}413.6U/mL$), and transudates ($273.6{pm}144.5U/mL$; all p<0.01). The serum levels were not significantly different among the disease groups. Based on receiver operating characteristics analysis, the area under the curve of M30 for differentiating tuberculous pleural effusion from all other effusions was 0.93. In the immunohistochemical analysis of M30, all pathologic types of cancer cells showed moderate to high expression, and the epithelioid cells in granulomas showed high expression in tuberculous pleural tissues. Conclusion: Caspase-cleaved cytokeratin 18 was most prominently observed in tuberculous pleural effusion and showed utility as a clinical marker. The main source of M30 was found to be the epithelioid cells of granulomas in tuberculous pleural tissues.