CYFRA 21-1 and CEA have been applied for the differential diagnosis of malignant pleural mesothelioma (MPM). The soluble mesothelin-related peptide (SMRP) has been proposed as a specific marker for distinguishing MPM from benign diseases and other malignancies in pleural effusions (PEs). In this study, we evaluated the usefulness of SMRP in PEs in the detection of mesotheliomas by comparing it with that of CYFRA 21-1, CEA, and with cytological examination. One hundred and seventy-seven consecutive patients (57 MPM, 64 metastatic tumors, and 56 benign diseases) were evaluated using commercial tests. The performance of the markers was analyzed by standard ROC analysis methods, using the area under a ROC curve (AUC) as a measure of accuracy. CYFRA 21-1 better differentiated malignant from benign effusions. The corresponding area under the receiver operating characteristic curve was 0.87, while it was 0.74 for SMRP and 0.64 for CEA (p < 0.001). Conversely, SMRP differentiated MPM from all other PEs better than both CYFRA 21-1 and CEA (AUC = 0.84, 0.76, and 0.32, respectively, p = 0.003). Low levels of CEA were associated with a MPM diagnosis. The AUC for differentiating MPM from metastases was 0.81 for SMRP, 0.61 for CYFRA 21-1, and 0.20 for CEA (p < 0.001). In cases with negative or suspicious cytology, SMRP and CYFRA 21-1 identified 36/71 and 46/66 malignant PEs (29 and 31 MPM, respectively). Only 1 MPM showed a high CEA concentration. No single marker showed the best performance in any comparison. Results suggest that SMRP could improve CYFRA 21-1 and CEA accuracy in the differential diagnosis of MPM.