Background: We explored whether biocompatible dialyzer membranes modulate the inflammatory response during blood contact in patients with systemic inflammation. Methods: 15 patients with end-stage renal disease and systemic inflammation (mean serum C-reactive protein 86 ± 4 mg/l) were randomly treated with Cuprophan (CU), polyamide (PA) and vitamin-E coated (VEC) membrane-based dialyzers. Results: Changes in blood pressure, capillary blood oxygen saturation and differential blood counts during the hemodialysis session were not significantly different between the three dialyzers. Baseline blood levels of activated circulating complement (C3a) were more than 100 times above normal, and unlike expected they decreased during hemodialysis treatments (CU: from 7,389 ± 783 to 5,423 ± 761 ng/ml; PA: from 7,379 ± 980 to 5,690 ± 714 ng/ml; VEC: from 7.377 ± 714 to 5,360 ± 1,005 ng/ml; all n.s.). No significant differences between treatments were found with respect to changes in blood concentrations of TNF-α, interleukin-6 and interleukin-1 receptor antagonist as well as ICAM-1 (CU: from 451 ± 41 to 477 ± 41 ng/ml; PA: from 437 ± 42 to 449 ± 40 ng/ml; VEC: from 461 ± 43 to 460 ± 47 ng/ml). Furthermore, generation of reactive oxygen species by mononuclear blood cells was comparable during hemodialysis with the CU, PA and VEC dialyzer. Conclusion: The choice of dialyzer membrane material does not affect most aspects of biocompatibility when patients have significant systemic inflammation. This confounding variable should be taken into account in studies exploring the effects of biocompatible dialyzer membranes.