Background: To evaluate the clinical performance of universal adhesives in etch-and-rinse or self-etch application modes through meta-analysis.Methods: A literature search was performed by two reviewers in the PubMed, Cochrane Library, and Embase databases (from January 2000 to March 2020). A total of 2,516 non-replicated records were identified and filtered. Studies that evaluated the clinical performance of universal adhesives using etch-andrinse or self-etch mode were included. RevMan 5.3.5 (Cochrane, London, UK) was used to perform the meta-analysis.Results: A total of 13 studies were included in the meta-analysis. The retention rates were higher in etchand-rinse groups compared with self-etch groups [odds ratio (OR) =0.35, 95% confidence interval (CI): 0.18-0.71, P=0.003]. The etch-and-rinse approach also had better performance in marginal adaptation (OR =0.49, 95% CI: 0.36-0.67, P<0.001) and marginal staining (OR =0.49, 95% CI: 0.36-0.66, P<0.001). The current data showed a very low incidence rate of secondary caries or postoperative sensitivity, and there were no significant differences in the incidence rates between the etch-and-rinse groups and self-etch groups.Discussion: The current evidence shows that, compared with self-etch approach, the etch-and-rinse approach for universal adhesives provides improved clinical outcomes in terms of retention rates, marginal adaptation, and marginal staining.