Objective To study the clinical value of isolated or combined detection of pro-gastrin-releasing peptide (ProGRP) and cytokeratin 19 fragment (CYFRA21-1) in pleural effusion in diagnosis for malignant hydrothorax caused by lung cancer. Methods Totally, 75 cases with malignant hydrothorax caused by lung cancer were divided into small cell lung carcinoma ( SCLC) group (n = 36) and non-small cell lung carcinoma ( NSCLC) group ( n = 39 ) , with 37 cases of benign hydrothorax as control. Isolated or combined ProGRP and CYFRA21-1 in pleural effusion were detected for them in diagnosis for malignant hydrothorax. Results Positive rate of ProGRP detection in pleural effusion was 91. 7% , 2. 6% and 2.7% for SCLC group, NSCLC group and benign group, respectively. Sensitivity of detection for malignant hydrothorax caused by SCLC was 91.7%, 55.6%, 82.1% and 13.5% by isolated CYFRA21-1, by isolated ProGRP, by combined ProGRP and CYFRA21-1 (in series) and by combined ProGRP and CYFRA21-1 (in parallel) in pleural effusion, respectively, and specificity of that was 97. 3% , 86. 5% , 97.3% and 83.8%, respectively, with Youden index of 0.889 6, 0.420 4, 0.473 0 and 0.782 3, respectively. Sensitivity of detection for malignant hydrothorax caused by NSCLC was 2. 6% , 82. 1 % , 2.6% and 82. 1% by isolated CYFRA21-1, by isolated ProGRP, by combined ProGRP and CYFRA21-1 (in series) and by combined ProGRP and CYFRA21-1 (in parallel) in pleural effusion, respectively, and specificity of that was 97.3%, 89.2%, 97.3% and 86.5%, respectively, with Youden index of -0. 0014, 0. 7124, -0. 0014 and 0. 6854, respectively. Sensitivity of detection for malignant hydrothorax caused by all lung cancer was 45. 3% , 69. 3% , 40. 0% and 98. 7% by isolated CYFRA21-1, by isolated ProGRP, by combined ProGRP and CYFRA21-1 (in series) and by combined ProGRP and CYFRA21-1 (in parallel) in pleural effusion, respectively, and specificity of that was 97.3%, 86.5%, 97.3% and 83.8%, respectively, with Youden index of 0.426 3, 0.558 2, 0.373 0 and 0.824 5, respectively. Conclusions Detection of ProGRP and CYFRA21-1 in pleural effusion was optimal choice of tumor markers for diagnosis of malignant hydrothorax caused by SCLC and NSCLC. Detection of both ProGRP and CYFRA21-1 in pleural effusion in parallel showed a better value in clinical diagnosis for malignant hydrothorax caused by lung cancer.