Introduction: Expanded hemodialysis (HDx) effectively removes large middle molecular uremic toxins (>25 kDa) while still retaining albumin, potentially reducing their adverse effects. We compare the clinical laboratory parameters, hospitalization rates, and medication use in a cohort of patients switched from high-flux HD to HDx. Methods: This is a multicenter, observational cohort study of 81 adult patients, across 3 clinics, with end-stage kidney disease (ESKD) on chronic hemodialysis (HD). Patients received high-flux HD for at least 1 year and then switched to HDx and were followed up for 1 year. Patients were excluded if they discontinued therapy, changed provider, underwent kidney transplant, recovered kidney function, or changed to peritoneal dialysis, another dialyzer, or renal clinic. Results: Twelve months after switching to HDx, the rate of hospitalization events per patient-year decreased from 0.77 (95% CI: 0.60–0.98, 61 events) to 0.71 (95% CI: 0.55–0.92, 57 events) ( p = 0.6987). The hospital day rate per patient-year was significantly reduced from 5.94 days in the year prior to switching compared with 4.41 days after switching ( p = 0.0001). The mean dose of erythropoiesis-stimulating agent (SC epoetin-α) and intravenous iron also significantly decreased ( p = 0.0361 and p = 0.0003, respectively). Conclusion: Switching to HDx was associated with reductions in hospital day rate and medication use, suggesting HDx has the potential to reduce the burden of ESKD on patients and healthcare systems.