Objective To evaluate the respective or synergistic value of cytoplasmic tryptophan-tRNA ligase （WARS1/SYWC） and adenosine deaminase （ADA） in diagnosing tuberculous pleural effusion （TPE）. Methods A retrospective analysis was conducted on 120 patients with pleural effusion （64 cases of TPE， 56 cases of non-TPE） admitted to the First Affiliated Hospital of Jinan University and its affiliated Shunde Hospital from January 2020 to December 2024. Pleural fluid SYWC levels were identified using enzyme-linked immunosorbent assay （ELISA）. Univariate and multivariate logistic regression analyses were performed to identify diagnostic predictors， while receiver operating characteristic （ROC） curves were plotted to assess the diagnostic performance of individual and combined biomarkers. Results Compared to the non-TPE group， TPE group exhibited significantly younger age， lower pleural CEA， less serum CEA， and lower neutrophil-to-lymphocyte ratio （NLR）， but significantly higher levels of pleural ADA， total protein， SYWC， and serum CRP （all P < 0.05）. Univariate analysis identified age， pleural CEA， carbohydrate antigen 199， ADA， SYWC， serum CEA， and NLR as potential predictors. Multivariate analysis confirmed pleural ADA （OR = 1.064， 95%CI：1.017 ~ 1.228） and SYWC （OR = 6.695， 95%CI：2.794 ~ 16.04） as independent diagnostic factors. At optimal cutoffs， SYWC （16.94 μg/L） demonstrated a sensitivity of 71.80% and specificity of 98.21%， while ADA （36.5 U/L） showed a sensitivity of 93.75% and a specificity of 89.29%. Combined detection increased the sensitivity to 95.56%， the specificity to 98.0%， and the accuracy to 97.87%. ROC analysis revealed an AUC of 0.973 （95%CI：0.943 ~ 1.000） for the combination， outperforming ADA （0.897） and SYWC （0.938） alone. Conclusion The combination of SYWC and ADA notably enhances diagnostic efficacy for TPE， providing high sensitivity and specificity as a reliable tool for clinical differentiation.