The diagnosis of pleural effusion is still difficult. The presence of pleural effusion can be confirmed by radiological studies including simple chest radiography, ultrasonography, or computed tomography. Identifying the causes of pleural effusions by pleural fluid analysis is essential. Aim of this work: The aim of this work is to assess the role of pleural fluid pH and pCO2 in differentiating the etiologies of pleural effusion and to study the correlation between pleural fluid pH and pCO2 and cellular content of the effusion. Results: We conducted this study on 50 patients with pleural effusions of different causes. The patients were classified into 5 groups according to the cause. For all the patients, measurement of pleural pH, pCO2, pO2, HCO3, protein, LDH, glucose and WBC was done. We observed lowest pH in complicated parapneumonic effusion (empyema) 6.80 ± 0.15 and highest pH was observed in transudative effusion 7.47 ± 0.07. Tuberculous effusion has pH lower than pH of malignant effusion 7.17 ± 0.017 and 7.39 ± 0.08, respectively. Post pleurodesis malignant effusion has pH lower than pH of malignant effusion 7.28 ± 0.17 and 7.39 ± 0.08, respectively. There is a strong inverse correlation between pH and pCO2, WBC, LDH and protein (r = −0.813 and p < 0.001), (r = −0.796 and p, 0.001), (r = −0.829 and p, 0.001) and (r = −.837 and p, 0.001), respectively. While there is a weak correlation between pH and glucose of pleural fluid (r = 0.249 and p = 0.066). The highest increase of PNL numbers was in empyema (20169 ± 8094.8 cells/cc).The highest increase of lymphocytes was in malignant effusions (4285.00 ± 2948.20 cells/cc) and tuberculous effusion (3977.7 ± 3169 cells/cc).