INTRODUCTION: The diagnostic utility of pleural fluid C-reactive protein (CRP) and procalcitonin (PCT) for parapneumonic pleural effusion (PPE) is a subject of ongoing investigation. There remains lack studies comparing their diagnostic accuracy in a head-to-head manner. Furthermore, the incremental diagnostic value of their combination over a single marker and the net benefit of them remains unknown. METHODS: This prospective study enrolled participants presenting with undiagnosed pleural effusion, subsequently measuring their pleural levels of CRP and PCT. A diagnostic model that integrated both biomarkers was constructed using logistic regression analysis. The diagnostic performance and net benefit of CRP, PCT, and the composite model were assessed through receiver-operating characteristic (ROC) curve analysis and decision curve analysis (DCA). RESULTS: The study included 32 PPE patients and 121 patients without PPE. The area under the ROC curve (AUC) for CRP was 0.73 (95% confidence interval [CI]: 0.63-0.83), with a sensitivity of 0.71 (95% CI: 0.55-0.87) and a specificity of 0.68 (95% CI: 0.59-0.77) at a threshold of 10 mg/L. In contrast, the AUC for PCT was 0.58 (95% CI: 0.46-0.69), with sensitivity and specificity rates of 0.50 (95% CI: 0.33-0.67) and 0.65 (95% CI: 0.56-0.74) at a threshold of 0.1 ng/mL, respectively. Notably, the AUC for the diagnostic model was comparable to that of CRP alone at 0.73 (95% CI: 0.63-0.82). DCA showed that applying CRP provided a net clinical benefit, while PCT did not. CONCLUSION: Pleural fluid CRP possesses moderate diagnostic capability for PPE, while PCT exhibits limited diagnostic utility. Additionally, the combined application of CRP and PCT does not confer any significant enhancement in diagnostic accuracy over the use of CRP alone.