Recently, circulating soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) was introduced as a potential biomarker which is downregulated in atherosclerosis. In the current study, we hypothesized that sTWEAK serum levels are decreased in end-stage renal disease and in patients with type 2 diabetes mellitus (T2DM) since both conditions are high-risk states for atherosclerotic disease. Soluble TWEAK was quantified by ELISA in control patients (n=60) with a glomerular filtration rate above 50 ml/min and patients on chronic hemodialysis (CD, n=60) and correlated to clinical and biochemical measures of renal function, glucose, and lipid metabolism, as well as inflammation. 30 control patients and 32 CD patients presented with T2DM. Mean serum sTWEAK concentrations were significantly lower in CD and T2DM patients with lowest concentrations seen when both conditions were present (control/-T2DM: 669 +/- 201 microg/l; control/+T2DM: 516 +/- 187 microg/l; CD/-T2DM: 402 +/- 128 microg/l; CD/+T2DM: 317 +/- 132 microg/l; all comparisons between groups p<0.05). In univariate analyses, sTWEAK was negatively correlated with fasting glucose in both, control and CD patients. In multivariate analyses, CD and T2DM remained independently associated with circulating sTWEAK. Taken together, circulating sTWEAK concentrations are decreased in end-stage renal disease and T2DM. Furthermore, both conditions have an additive and independent negative effect on sTWEAK levels. Our results support the view that circulating sTWEAK might be a novel biomarker of atherosclerosis.