Many studies have proved that carcinoembryonic antigen (CEA) and cancer antigen 125 (CA125) have high affinity and binding specificity, and can be used to distinguish pleural effusion in patients with malignant and non-malignant pleural effusion. So, investigated whether tumour markers carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), cancer antigen 125 (CA-125), and cytokeratin 19 fragment (CYFRA 21-1) in pleural effusions and serum is most important. Patients and methods: This Observational Descriptive Cross Section study. was carried out in Chest diseases department at Zagazig University Hospitals on 70 cases with pleural malignancies started from June Months 2023 to January 2024. Pleural fluid CEA was done using electrochemiluminescence immunoassay (ECLIA) (Sandwich principle). CA125 was measured in pleural fluid in U/ml using the commercially available ELISA kit. Results: There was a significant higher cancer antigen 125 and a carcinoembryonic antigen in malignant compared to benign pleural effusion. Cancer Antigen 125 (Ca125) at cut off ≥12 and carcinoembryonic antigen at cut off level ≥3: show sensitivity 97.1%, specificity 60.0% and accuracy 78.6% to discriminate malignant pleural effusion from benign pleural effusion. This indicated that both cancer antigen 125 (Ca125) & carcinoembryonic antigen give highly suspicious of malignancy but poor specificity. Conclusions: In cases of malignant effusion the level of Ca-125 and CEA are significantly higher in pleural fluid. CA125, and CEA markers proved to be highly effective as malignant markers, might be useful in the differentiation between malignant and benign effusions.