(1) Background: Malignant (MPE), parapneumonic (PPE) and tuberculous (TPE) pleural effusions constitute common causes of pleurisy. Discriminating among them is usually challenging. C-reactive protein (CRP) and adenosine deaminase (ADA) pleural levels (p-CRP, p-ADA) have been used as differentiators in many studies showing promising results. This study aims to evaluate the diagnostic value of p-CRP, p-ADA levels and their combination among the three categories. (2) Methods: A prospective study of 100 patients with MPE (n = 59), PPE (n = 34) and TPE (n = 7) from a single centre was performed. p-CRP levels were evaluated between PPE and non-PPE and between complicated (CPPE) and non-complicated PPE. ADA levels were also measured to classify patients among MPE and non- MPE. Eventually, the combination of p-CRP and p-ADA values was used as a discrimination factor among PPE, MPE and TPE. (3) Results: ROC analysis revealed that p-CRP with a cut-off value: 4.4 mg/dL can successfully differentiate PPE (AUC = 0.998). The cut-off level of 10 mg/dL can predict CPPE with sensitivity: 63%, specificity: 71.4%, positive predictive value (PPV): 89%, and negative predictive value (NPV): 33%. Furthermore, patients with ADA levels ≤ 32 U/L were more likely to belong to the malignant group sensitivity: 93%, specificity: 78%, PPV: 85.9%, and NPV: 88.9%. Discriminant analysis showed that the combination of p-CRP and p-ADA levels can discriminate PPE, MPE and TPE in 93% of cases. (4) Conclusion: This study provides evidence that p-CRP and p-ADA levels could be possibly used in clinal practice in order to establish a diagnosis among MPE, PPE and TPE.