Long-term hemodialysis (HD) induces an inflammatory response and is associated with a suppressed cellular immune response manifested, in part, by impaired interferon (IFN-γ) production. We investigated the effect of high-flux HD using the synthetic Helixone<sup>®</sup> membrane and ultrafiltered dialysate on plasma levels of inflammatory mediators and on the whole blood production of IFN-γ. Methods: Twelve ESRD patients were dialyzed under low-flux HD (polysulfone F6) and again after 6 weeks of high-flux HD (Helixone<sup>®</sup> FX100). Ultrafiltered bicarbonate dialysate without bacterial growth and no detectable endotoxin was used throughout the study. Plasma levels of urea, albumin, β<sub>2</sub>-microglobulin (β<sub>2</sub>-m), interleukin (IL)-6, C-reactive protein (CRP), IL-1 receptor antagonist (IL-1Ra), IL-18, and IL-18-binding protein (IL-18BP) were measured. In addition, the Staphylococcus epidermidis-induced production of IFN-γ and IL-18 was assessed in whole blood cultures of HD patients as well as in 9 healthy subjects. Results: Plasma levels of urea, albumin, IL-6, IL-1Ra and CRP were not significantly different between high-flux and low-flux HD. In contrast, β<sub>2</sub>-m levels decreased significantly by 31% with high-flux Helixone<sup>®</sup> (p < 0.002). Stimulated whole blood production of IFN-γ was reduced in low-flux HD but increased to near normal levels after 6 weeks of high-flux HD. Plasma levels of free IL-18 and its specific inhibitor IL-18BP were not different between the two dialyzer membranes. Conclusion: Compared to low-flux polysulfone HD with ultrafiltered dialysate, high-flux HD with the synthetic Helixone<sup>®</sup> membrane did not result in a significant change in plasma levels of proinflammatory (IL-6, CRP, IL-18) and anti-inflammatory (IL-1Ra, IL-18BP) cytokines. However, high-flux HD restores whole blood IFN-γ production without significant changes in free IL-18. Therefore, the immune modulation in high-flux HD is likely due to removal of inhibitors of IFN-γ production other than IL-18BP.