The immune response requires the coordinated release of a network of cytokines including interleukin-1 (IL-1), tumor necrosis factor (TNF), and IL-2. The potential role of the dialysis membrane on the elaboration of these cytokines by peripheral blood mononuclear cells (PBMNC) harvested from hemodialysis patients was investigated in a prospective crossover study. Eight hemodialysis patients, chronically dialyzed with a biocompatible membrane, were sequentially dialyzed for 2 wk with new cuprophane membranes (Phase I), 2 wk with a low-flux, low-complement-activating membrane (Phase II), and then switched back for a further 2 wk of dialysis with a cuprophane membrane (Phase III). At the end of 2 wk of exposure to the cuprophane membrane, during both Phase I and Phase III, the ability of PBMNC to elaborate IL-1 beta, tumor necrosis factor-alpha, and IL-2, as well as soluble IL-2 receptors, in response to phytohemagglutinin was significantly reduced compared with their respective levels at the beginning of the phase; dialysis with a biocompatible membrane increased these levels, and at the end of 2 wk, the response of the PBMNC to phytohemagglutinin was close to that in normal controls. These findings may explain some of the conflicting results in the measurement of cytokine levels in hemodialysis patients and may have clinical implications.