A high venous plasma norepinephrine (NE) level is a predictor of poor prognosis in congestive heart failure (CHF). To evaluate the mechanisms responsible for the high plasma NE in CHF, NE kinetics were studied in 19 patients with CHF and 18 normal subjects during a 90-min steady-state intravenous infusion of tracer [3H]NE of high specific activity. Venous plasma NE between 70 and 90 min of infusion was significantly higher in the CHF patients (CHF, 634, and normal, 247 pg/ml; P less than 0.001). The following equations were used: NE clearance = [3H]NE infusion rate (dpm/min)/plasma [3H]NE (dpm/l), and NE spillover = [3H]NE infusion rate (dpm/min)/[3H]NE specific activity (dpm/nmol). In CHF, a decreased clearance and an increased spillover contributed nearly equally to the high plasma NE (NE clearance: CHF, 0.99; normal, 1.48 l.min-1.m-2; P less than 0.001; NE spillover: CHF, 3.60; normal, 2.08 nmol.min-1.m-2; P less than 0.001). These data document that both NE clearance and NE spillover are abnormal in CHF, and they raise the new possibility that the factors responsible for the reduced NE clearance could be related to the factors linking a high plasma NE with early mortality.