Inactive plasma renin (a prorenlp-like substance) can be activated by trypsin. There are also endogenous neutral serine proteases in plasma that can activate inactive renin in vitro, but only after protease inhibitors are either destroyed by acidification (the alkaline phase of acid activation) or inactivated by cold (cryoactivation). In the present study we have shown that cold also facilitates trypsin activation. But even at-4 C, as much as 1 rag/ral of trypsin was required to overcome endogenous inhibitors and reproducibly activate inactive plasma renin during a 1-hour incubation at pH 7.4. After partial destruction of plasma protease inhibitors by acidification to pH 33., less trypsin was required for complete activation at pH 7.4: 200 Mg/ml at 25 C and 100 Mg/ml at-4 C. In contrast, 10 fig/ml of the renal enzyme urinary kallikrein completely activated inactive renin in previously acidified plasma at 25 C. Maximum activation of inactive plasma renin by either trypsin or renal kallikrein was almost identical. Both enzymes caused activation in plasmas deficient in Hageman factor or Fletcher factor (prekallikrein), suggesting that their ability to activate inactive renin is not mediated by these neutral serine proteases of the intrinsic coagulation system. Using maximum trypsin activation to define" total" renin, we found that among 22 normal subjects and hypertensive patients there was a direct relationship between the proportion of active renin in plasma (active/total) and the concurrent urinary kallikrein excretion (r= 0.46, p< 0.05). Normotensive white subjects had a higher proportion of active plasma renin than blacks, in whom urinary kallikrein is reported to be low. Altogether, these data suggest that there might be a link between prorenin and renal kallikrein in vivo. Further studies are required to evaluate this possibility and to determine whether prior hydrolysis of inactive renin, for example, by acidification, is required for renal kallikrein to activate inactive renin.(Hypertension 1: 179-189, 1979)