Congestive heart failure is characterized by decreased cardiac output and increased peripheral vascular resistance. Endothelin, a peptide found in plasma, is a potent vasoconstrictor. We hypothesized that plasma concentrations of endothelin are increased in humans with congestive heart failure. Plasma samples were obtained from 71 healthy control subjects and 56 patients with congestive heart failure. The mean plasma concentration of endothelin, measured by radioimmunoassay, was 7.1 +/- 0.1 pg/ml in the 71 normal control subjects but 12.6 +/- 0.6 pg/ml in the 56 patients with heart failure (P = 0.001). To evaluate the relationship between circulating endothelin and clinical stage of congestive heart failure, we categorized patients into two groups--those with mild heart failure (New York Heart Association class I or II) and those with severe heart failure (class III or IV). Circulating endothelin in the 24 patients with mild disease was 11.1 +/- 0.7 pg/ml, significantly higher than in normal subjects (P < 0.001). Endothelin in the 32 patients with severe heart failure was 13.8 +/- 0.9 pg/ml, a level significantly higher than that in the group with mild disease (P = 0.029). In the 56 patients with congestive heart failure, a negative correlation was found between plasma concentration of endothelin and left ventricular ejection fraction (r = -0.279; P = 0.037). These data demonstrate that the plasma concentration of endothelin is increased in humans with congestive heart failure and that the level correlates with the severity of disease. Endothelin may have a role in the increased vascular resistance in patients with chronic congestive heart failure.