Objective To study whether serially measured plasma concentrations of endothelin (a novel, potent, endogenous vasoconstrictor derived from endothelium and macrophages) relate to the pathophysiology and severity of human septic shock. Design Prospective analysis. Setting Medical ICU of a university hospital. Patients Six patients with septic shock, studied for 8 days after ICU admission. Measurements and Main Results The initial plasma endothelin concentration was increased (14.2 ± 5.2 [SD] vs. normal 4.2 ± 0.7 pg/mL, p < .05) and correlated with the Acute Physiology and Chronic Health Evaluation II score (r2 = .79, p < .05). For pooled data, endothelin levels correlated poorly with leukocyte counts (r2 = .13), mean arterial pressure (MAP) (r2 = .16), and administered doses of dopamine (r2 = .26). In multiple regression analyses, plasma endothelin concentrations were predicted by dopamine doses and not by MAP. Plasma endothelin concentrations predicted the decrease in creatinine clearance, independently from MAP. The pooled value for correlations between endothelin levels and creatinine clearance, during the course of disease in individual patients, was statistically significant (r2 = .31). Conclusions During septic shock, the release or production of endothelin may increase as a consequence of endothelial injury by activated leukocytes and the infusion of catecholamines, and this mechanism may relate to renal vasoconstriction and to the severity of disease. (Crit Care Med 1992; 20:1097–1101)