The level of tumor necrosis factor alpha (TNF-alpha) is increased in patients with congestive heart failure and may play an important role in the development and progression of heart failure. Two types of TNF receptor (TNF-RI and TNF-RII) are expressed in virtually every cell and have different biologic roles. Soluble forms of the two receptors (sTNF-RI and sTNF-RII) have been identified as extracellular domain fragments. Serum levels of TNF-alpha, sTNF-RI and sTNF-RII were measured in 66 patients with heart failure and 27 control subjects using an enzyme-linked immunosorbent assay (ELISA). Hemodynamic variables, norepinephrine, atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP) were evaluated. TNF-alpha was significantly higher in patients with heart failure than in controls subjects (9.4 +/- 1.4 vs 4.8 +/- 0.8 pg/ml; p < 0.05). sTNF-RI and -RII were significantly increased in relation to the severity of heart failure (control subjects, 0.66 +/- 0.04 and 1.97 +/- 0.15 ng/ml; NYHA class II, 1.10 +/- 0.08 and 2.28 +/- 0.12 ng/ml; NYHA class III, 1.63 +/- 0.22 and 3.00 +/- 0.24 ng/ml; NYHA class IV, 2.78 +/- 0.46 and 4.52 +/- 0.62 ng/ml, respectively). In 9 patients whose clinical symptoms improved after treatment, the levels of sTNF-RI and -RII decreased by 17.3 +/- 5.7% (p < 0.05) and 22.1 +/- 6.9% (p < 0.05), respectively. There were significant positive correlations between sTNF-RI and -RII and mean pulmonary pressure (r = 0.69 and r = 0.61; p < 0.001) and mean capillary wedge pressure (r = 0.65 and r = 0.54; p < 0.001 and p < 0.01, respectively), but not with left ventricular end-diastolic volume or ejection fraction (NS). sTNF-RI and -RII were also significantly positively correlated with plasma levels of norepinephrine (r = 0.75 and r = 0.50; p < 0.001 and p < 0.05), ANP (r = 0.72 and r = 0.70; p < 0.001), and BNP (r = 0.60 and r = 0.60; p < 0.001). In conclusion, soluble TNF receptors are increased in proportion to the severity of congestive heart failure and may reflect the current status of congestive heart failure rather than the level of left ventricular dysfunction.