BACKGROUND: Biomarkers in pleural fluid are the potential auxiliary diagnostic markers for malignant pleural effusion (MPE). Exosomal microRNAs (miRNAs) represent novel diagnostic markers for various diseases. The diagnostic performance of exosomal miRNAs for MPE remains unclear. Therefore, we examined the exosomal miRNAs profiles of both MPE and benign pleural effusion (BPE), aiming to study diagnostic performance of exosomal miRNAs for MPE. METHODS: We used next-generation sequencing (NGS) technology to analyze the pleural fluid exosomal miRNA profile in five MPE and 15 BPE cases. We analyzed the differentially expressed exosomal miRNAs by reverse transcription polymerase chain reaction (RT-PCR), with cel-miR-39 or snRNA U6 as internal references. We assessed the diagnostic accuracy of exosomal miRNA for MPE with a receiver operating characteristic (ROC) curve. We also analyzed whether exosomal miRNA could improve the diagnostic performance of pleural carcinoembryonic antigen (CEA). RESULTS: Fifty-eight miRNAs were up-regulated, and 35 miRNAs were down-regulated in MPE. We selected exosomal miR-182-5p for further study and analyzed miR-182-5p in 153 patients with undiagnosed pleural effusion. Exosomal miR-182-5p was undetectable in 32 participants. In the remaining participants with 49 MPE and 72 BPE cases, we found that the areas under the curve (AUCs) and their 95% confidence intervals (95% CIs) for exosomal miR-182-5p were 0.78 (95% CI: 0.69-0.86) when using cel-miR-39 as an internal reference, and 0.80 (95% CI: 0.73-0.88) when using snRNA U6. The combination of exosomal miR-182-5p and CEA can slightly improve the diagnostic accuracy of MPE, with an AUC of 0.91 (95% CI: 0.85-0.97). CONCLUSIONS: Pleural miR-182-5p can assist in the diagnosis of MPE. Its diagnostic performance is slightly affected by internal reference.