Background The diagnosis of malignant pleural mesothelioma (MPM) is generally difficult, and no single biomarker has been established. Hyaluronic acid (HA) is highly elevated in MPM and could thus be a diagnostic biomarker. However, to our best knowledge, no systematic review has evaluated the diagnostic accuracy of pleural HA. This systematic review aimed to evaluate the diagnostic accuracy of pleural effusion HA for MPM. Method We searched MEDLINE via OVID, Embase via Embase.com, Central, and the International Clinical Trials Registry Platform databases for relevant articles. Prospective, retrospective, and case control studies that assessed the sensitivity and specificity of pleural effusion HA for MPA diagnosis were included. The exclusion criteria were review articles, case reports, and animal studies. The quality of the included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Forest plots were generated to summarize the sensitivity and specificity of HA in each included study. In addition, the pooled sensitivity and specificity of HA for MPA diagnosis was calculated using a bivariate random effects model. Result Overall, 6 studies involving 1,548 patients were included. There was a high risk of bias because 83% of the included studies had a case control design. The pooled sensitivity and specificity were 50% (95% CI: 40-59%) and 97% (95% CI: 93-99%), respectively. We could not obtain a reliable estimate of the 95% confidence region or 95% prediction region because of the small sample sizes of the included studies. Conclusions Although HA in pleural effusion might have low sensitivity and high specificity for MPM diagnosis, we could not draw a valid conclusion because of the high risk of bias and small sample size. Further large scale retrospective cohort studies are needed to more accurately estimate its sensitivity and specificity.