Background: The differential diagnosis of tuberculous pleural effusion (TPE) and malignant pleural effusion (MPE) is difficult because the biochemical profiles are similar. The present study aimed to differentiate TPE from MPE, using a decision tree and a weighted sparse representation-based classification (WSRC) method, based on the best combination of routine pleural effusion fluid biomarkers. Materials and Methods: The routine biomarkers of pleural fluid, including differential cell count, lactate dehydrogenase (LDH), protein, glucose and adenosine deaminase (ADA), were measured in 236 patients (100 with TPE and 136 with MPE). A Sequential Forward Selection (SFS) algorithm was employed to obtain the best combination of parameters for the classification of pleural effusions. Moreover, WSRC was compared to the standard sparse representation-based classification (SRC) and the Support Vector Machine (SVM) methods for classification accuracy. Results: ADA provided the highest diagnostic performance in differentiating TPE from MPE, with 91.91% sensitivity and 74.0% specificity. The best combination of parameters for discriminating TPE from MPE included age, ADA, polynuclear leukocytes and lymphocytes. WSRC outperformed the SRC and SVM methods, with an area under the curve of 0.877, sensitivity of 93.38%, and specificity of 82.0%. The generated flowchart of the decision tree demonstrated 87.2% accuracy for discriminating TPE from MPE. Conclusion: This study indicates that a decision tree and a WSRC are novel, noninvasive, and inexpensive methods, which can be useful in discriminating between TPE and MPE, based on the combination of routine pleural fluid biomarkers.