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Background: Malignant pleural effusion (MPE) is a common medical problem caused by multiple malignancies, especially lung cancers, and always comes along with a poor outcome. Early detection and diagnosis are important for improving the prognosis in patients with MPE. Salivary microRNAs (miRNAs) may represent a relatively convenient way for diagnosing MPE. We investigated the characteristics of salivary miRNAs of MPE patients, benign pleural effusion (BPE) patients, patients with a malignant tumor but without pleural effusion (MT), and healthy controls (HCs). We believe that they may show potential as a non-invasive and convenient biomarker for diagnosing MPE., Methods: From January 1, 2019, to July 1, 2019, 57 MPE patients, 33 BPE patients, 50 MT patients, and 49 HCs were enrolled. To select candidate biomarkers, in the discovery phase, the salivary miRNA profiles were detected in three MPE patients and three HCs. Then, qPCR was used in the validation phase with 54 MPE patients, 33 BPE patients, 50 MT patients, and 46 HCs to assay the selected miRNAs., Results: hsa- miR-4484 and hsa- miR-3663-3p were identified as potential biomarkers to diagnose MPE patients, with areas under the curve (AUC) of 0.768 and 0.666, respectively. The diagnostic efficacy was higher when the combination of both miRNAs was used, with an AUC of 0.802. No correlation was found between the volume of MPE and the expression of salivary miRNAs., Conclusions: This study reports the characterization of salivary miRNAs collected from MPE patients. A combination of hsa- miR-4484 and hsa- miR-3663-3p showed potential discriminatory power for MPE detection, and it may be helpful for the early diagnosis of MPE, i.e., before the pleural effusion volume is too large., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-19-530). The authors have no conflicts of interest to declare., (2020 Translational Lung Cancer Research. All rights reserved.)