Chemical pleurodesis using various sclerosing agents is accepted palliative therapy for patients with recurrent, symptomatic, malignant pleural effusions (MPE). However, the utility of various clinical and biochemical parameters in predicting pleurodesis outcome is still controversial. The objective of this study was to investigate the relationship between pleural fluid adenosine deaminase (Pf-ADA) levels and talc pleurodesis outcomes, and to compare Pf-ADA levels to various other biochemical variables with respect to predicting talc pleurodesis outcome in patients with MPE. In this prospective trial, 60 consecutive patients with MPE were enrolled; 35 had malignant mesothelioma (MM) and 25 had metastatic pleural carcinoma (MPC). A complete response was achieved in 49 of 60 MPE patients (81.7%). The Pf-ADA, pH, and albumin levels in patients with successful pleurodesis were significantly higher than in those with unsuccessful pleurodesis (p values < 0.001, 0.036, 0.027, respectively). ROC curve analysis revealed that optimal differentiation between successful and unsuccessful pleurodesis could be achieved with cutoff points of 17.5 U/L for Pf-ADA (area under the curve = 0.873; sensitivity = 77.6%; specificity = 90.9%); >2.5 g/dl for albumin (area under the curve = 0.715; sensitivity = 85.4%; specificity = 54.5%); and >7.26 for pleural fluid pH (area under the curve = 0.703; sensitivity = 83.7%; specificity = 54.5%). In analysis of the subgroup, Pf-ADA were found to be a good marker for discrimination between successful and unsuccessful pleurodesis in patients with MM (p < 0.001) but not in the MPC group (p = 0.068). These results indicate that Pf-ADA levels could be considered predictors of the outcome of pleurodesis, especially in patient with MM. Furthermore, the present study also demonstrated that Pf-ADA level is a superior test to predict the outcome of pleurodesis compared to pleural fluid pH and albumin level.