Trypsinization of human plasma, like acid activation or cryoactivation, increases renin activity, as determined by subsequent enzymatic assay. In three plasma pools, tryptic activation was maximal within 2 min at a trypsin concentration of 500 micrograms/ml, decreasing at higher concentrations. Neither prolongation of trypsin exposure for up to 1 h nor temperature (0 or 37 C) mattered. In plasmas from 26 healthy volunteers ambulatory for 3 h, trypsin increased PRA 3-fold from 2.8 +/- 0.4 to 8.3 +/- 0.7 ng/ml.h (P less than 0.001). Plasma renin reactivity (the amount of angiotensin I generated in plasma by the addition of active renin) and plasma renin substrate were unaltered by trypsin in concentrations up to 500 micrograms/ml. By exclusion, these data support the concept that an inactive precursor form of renin normally exists in human plasma. At concentrations of trypsin of 1 mg/ml or greater, tryptic activation diminished due to degradative effects of trypsin on the renin assay system, indicating the need for careful selection of conditions to maximize tryptic activation.