Background: The concentration assay of pleural effusion interleukin-27 (IL-27) has raised concern for diagnosing tuberculous pleurisy. Compared with malignant pleural effusion (MPE), the concentration of IL-27 in tuberculous pleural effusion (TPE) increased significantly. Accurate differentiating diagnosis is essential for choosing treatment for pleural effusion. Objective: The present meta-analysis is aimed at determining the accuracy of IL-27 in the differential diagnosis between TPE and MPE. Material andMethod: After having retrieved the published studies, we combined the sensibility (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) of IL-27 in the diagnosis of TPE compared to MPE using a fixed-effect model. The summary receiver operating characteristic curve was applied to estimate the overall test performance. Results: In total, 550 patients (285 patients with TPE and 265 patients with MPE), included in 7 case-control studies, were enrolled. The summary assessments for IL-27 in the diagnosis between TPE and MPE were: SEN 0.93 (95% CI 0.90–0.96), SPE 0.97 (95% CI 0.94–0.98), PLR 25.88 (95% CI 13.84–48.39), NLR 0.07 (95% CI 0.05–0.11), and DOR 333.26 (95% CI 146.10–760.19), respectively. The maximal joint SEN and SPE was 0.95; the area under the curve was 0.99. Conclusion: IL-27 determination is a relatively accurate test for the diagnosis of TPE, which has very high SEN and SPE for discriminating TPE from MPE. The results of IL-27 assays should be interpreted in parallel with clinical findings and the results of conventional tests.