It has previously been suggested that in addition to renin and renin substrate concentrations, other factors in plasma may also influence the rate of angiotensin production. The present study was performed to compare the reactivity of exogenous renin in plasma of normal subjects with that in plasma of hypertensive patients and uremic patients. During a 30-min in vitro incubation after the addition of exogenous renin, angiotensin I generation, determined by radioimmunoassay, in plasma of patients with essential hypertension (28.0 ng/ml ± 2.1 se) was greater than that of normal subjects (22.6 ng/ml ± 1.3 se). Angiotensin generation was more strikingly increased in plasma of uremic patients (41.0 ng/ml ± 3.6 se) and patients with renovascular hypertension (32.0 ng/ml ± 2.8 se). These differences are not related to differences of endogenous renin activity, renin substrate concentration, or angiotensinase activity. Plasma from normal subjects, but not from uremic patients or from patients with renovascular hypertension, significantly decreased the velocity of the renin reaction in a renin- renin substrate system. This suggests that normal plasma contains a factor, not present in renovascular hypertensive or uremic plasma, that inhibits the renin reaction.