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Expanded hemodialysis (HDx), using medium cut‐off membrane, is a novel therapy that effectively clears middle molecules (MMs). We aimed to compare HDx to hemodiafiltration (HDF) in an open randomized clinical study. Patients currently on HDF (age 18–80 years; on HDF >3 months) were randomized to switch to HDx (N = 21) or continue HDF (N = 22) with a 24‐week follow‐up. Pre‐ to post‐dialysis reduction ratios (RR) and changes in pre‐dialysis levels over time were evaluated for MMs and clinical biomarkers. Use of erythropoiesis‐stimulating agents (ESAs) was assessed. HDx showed greater RR for YKL‐40 while RR appeared similar between groups for beta2‐microglobulin, FGF‐23, and free light chains. Intradialytic changes in inflammatory biomarkers (IL‐6, CRP, PTX3) did not differ between therapies. Changes from baseline to 12 and 24 weeks did not differ between groups for MMs, inflammatory markers, albumin, fibrinogen, hemoglobin, PTH, and phosphorus. Use of ESAs tended to decrease in HDx arm while remaining stable in HDF arm. HDx appeared safe with similar clinical effectiveness as HDF. With fewer requirements and resource needs, HDx provides an attractive alternative to HDF. [ABSTRACT FROM AUTHOR]