Patients with chronic congestive heart failure are known to have increased plasma norepinephrine and plasma renin activity. In order to evaluate neurohumoral changes over time, we measured plasma norepinephrine and plasma renin activity at baseline and sequentially during follow-up in 49 patients with chronic, stable congestive heart failure. All patients were treated with digitalis and diuretics. Converting enzyme inhibitor therapy was prescribed as adjunctive therapy in 22 patients, while 10 patients were taking hydralazine and/or isosorbide dinitrate, seven were taking prazosin, and 10 had no adjunctive therapy. Patients were divided into those taking converting enzyme inhibitors (group I, n = 22) and those not taking converting enzyme inhibitors (group II, n = 27). Group I was followed for a median (25th to 75th percentiles) of 24.3 (18 to 27.9) months, while group II was followed for 18.7 (11.9 to 36.5) months. Results indicate that patients in group I demonstrate a significant positive trend for rise in plasma norepinephrine of 11.7 pg/ml per month (7.8 to 15 pg/ml per month, 95% confidence interval). Patients in group II also demonstrated a significant positive trend in plasma norepinephrine over time of 6.6 pg/ml per month (2.2 to 11.1 pg/ml per month). Moreover, there was a progressive trend upward in plasma renin activity over time in group II (median 0.34 ng/ml/hr per month; range 0.13 to 0.54). The data indicate that there is a significant trend of neurohumoral activation over time in patients with chronic, clinically stable congestive heart failure. The increase in plasma norepinephrine does not appear to be prevented by chronic converting enzyme inhibitor therapy, although these data cannot rule out the possibility of a reduced slope compared to a control group.