Background and aim <p>The comparison between online hemodiafiltration (online HDF) and expanded hemodialysis (HDx) remains undetermined. This systematic review and meta-analysis were conducted to provide comparative evidence on the molecule clearance, efficacy, and all-cause mortality of HDx versus online HDF in patients with end-stage kidney disease (ESKD).</p> Materials and methods <p>A comprehensive search was conducted up to September 10, 2024, using various electronic databases PubMed, Cochrane Library, Scopus, Web of Science, and Ovid MEDLINE with adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Risk ratios (RR) for binary outcomes and standardized mean differences (Hedge’s <i>g</i>) were used for continuous outcomes.</p> Results <p>The meta-analysis included eight studies, consisting of 614 patients in total. No statistical difference in all-cause mortality was found between HDx and online HDF (RR 0.97; 95% Cl 0.62–1.53, <i>p</i> = 0.91, <i>I</i>² = 0%). Online HDF revealed a decrease in β2-microglobulin clearance (Hedges’s <i>g</i> = −&#xa0;0.61, 95% CI −&#xa0;1.04 to −&#xa0;0.18, <i>p</i> = 0.01), with no differences in creatinine, phosphate, and urea clearance. Prolactin clearance favored online HDF (Hedge’s <i>g</i> = −&#xa0;1.49, 95% Cl −&#xa0;3.36 to 0.37, <i>p</i> = 0.12) but the pooled estimate remained insignificant, with high heterogeneity (<i>I</i>² = 90.87%).</p> Conclusion <p>Overall, both modalities are found to be effective, but online HDF revealed superior efficacy with potential advantages in middle-molecule clearance. Further standardized, randomized, and high-quality trials are required not only to confirm these findings but also to address the substantial heterogeneity found in the clearance of prolactin, myoglobulin, and albumin loss.</p> Registration <p>PROSPERO registration number: CRD42024622632.</p>