Acid activation of plasma prorenin occurs during dialysis to pH 3.3. and also during subsequent dialysis to pH 7.4. The latter, alkaline phase, involves Hageman factor-dependent formation of kallikrein, which in turn activates prorenin. The present study evaluates whether prorenin activation always occurs whenever kallikrein is activated in plasma. TAME esterase activity was used as a measure of plasma kallikrein activity an increase was observed during the alkaline phase of acid activation of prorenin. TAME esterase activity was absent when Hageman factor- or prekallikrein-deficient plasmas were similarly assayed and prorenin was not activated. Kaolin treatment of normal plasma rapidly increased TAME esterase activity at both 25 degrees and -4 degrees C, but no prorenin activation occurred. Similar changes in TAME esterase activity were observed in acid-treated plasma, in which setting prorenin was activated. No change in TAME esterase or renin activity occurred after addition of kaolin to acid-treated plasma deficient in Hageman factor; however, both enzymatic activities increased slightly in acidified prekallikrein-deficient plasma. Mixtures of these deficient plasmas exhibited normal kaolin activation of both TAME esterase and prorenin after acidification. Thus both Hageman factor and prekallikrein are needed for optimal contact activation of prorenin. These results demonstrate that prorenin activation does not always occur when active kallikrein is present in plasma. Prior acidification appears to be a prerequisite. Acidified prorenin may be more susceptible to cleavage; alternatively, competing substrates and/or inhibitors of kallikrein may be destroyed at acid pH, thereby permitting kallikrein to activate prorenin. Under normal conditions, activation of the plasma kallikrein-kinin system appears unlikely to result in activation of prorenin in vivo.