Patients on hemodialysis suffer from an impaired immunity against infectious agents, hyporesponsiveness to vaccination and are prone to develop malignancies. This clinical state of immunoincompetence may be due to a disbalance in their defense mechanisms in which TNF-alpha and its soluble receptors 1 and 2 play a central role. We measured, with double-sandwich ELISA, the levels of TNF-alpha and the soluble TNF-receptors in peripheral blood of patients on chronic intermittent hemodialysis (CIHD), on peritoneal dialysis (CAPD) and pre-dialysis end-stage renal failure (ESRF). Using reverse transcriptase polymerase chain reaction (RT-PCR) analysis, we quantified the amount of TNF-alpha mRNA in peripheral blood mononuclear cells (PBMC) obtained from these patient groups. In none of the patient groups, elevated levels of TNF-alpha were detected with ELISA, while high levels of soluble TNF receptors were present in ESRF, CAPD and CIHD patients. This may be the result of an activated TNF-alpha system or due to their impaired renal clearance. TNF-alpha mRNA level was elevated in CIHD patients compared to ESRF and CAPD patients or healthy controls. This suggests that only during chronic HD is the TNF-alpha system activated. High levels of sTNFR, found in ESRF or CAPD patients do not reflect activation of TNF-alpha system, but are the result of impaired renal clearance of the receptors. Indeed, we found a strong linear correlation between the levels of sTNF receptors and renal function. Nevertheless, these high levels of sTNF receptors are biological active, as they were able to bind active TNF-alpha up to 75% (range 46 - 83%) and thus inhibit the bioactivity and bioavailability of produced TNF-alpha. This may play a role in the immunoincompetence of these patients.