Malignant pleural mesothelioma (MPM) is a rare form of thoracic malignancy with a poor prognosis. Pleural effusion (PE) occurs in the majority of patients with MPM; however, its impact on MPM outcomes remains controversial. We searched for eligible patients from the Surveillance, Epidemiology, and End Results (SEER) database, and clinicopathological information and outcomes were collected. Cox proportional hazard regression analyses were utilized to evaluate the association of PE and other factors with overall survival (OS) and cancer-specific survival (CSS) in patients with MPM. A total of 4185 patients were extracted from the SEER database from 2000 to 2021. The median age of the cohort was 73 years, with a predominance of male patients and epithelioid MPM as the main histological subtype. Univariate Cox regression revealed associations between PE, age, sex, marital status, histology, stage, and treatment with both OS and CSS. Besides, multivariate analyses indicated that PE was independently associated with poorer OS and CSS in patients with MPM, regardless of age, sex, histology, stage, and treatment. Subgroup analyses suggested that PE has a remarkable impact on patients undergoing surgery. PE might serve as an independent prognostic factor in patients with MPM, especially in surgery recipients. Consequently, the development of pleural effusion in these patients should receive increased attention. Future studies are needed to validate these findings, particularly concerning the effect of PE in other clinical settings, such as immunotherapy.© 2024. The Author(s).