Immunization with renin from the kidneys of hog, beef, dog, rabbit and man induced the formation of a highly active enzyme (enzyme I) in the serum of dogs, guinea pigs, rabbits and rats. Enzyme I produces angiotensin I maximally at pH 4.7, up to 2900 ng/ml serum/h, i.e. at a rate 2500 times higher than the endogenous renin of normal serum. At pH 7.2 the angiotensin I production by enzyme I is about 16 to 28 times higher than that of plasma renin. Enzyme I is produced by immunization with renin and not by other kidney proteins. Enzymatically-active renin is required and separate mechanisms are involved in the formation of enzyme I and antirenin. Enzyme I is not identical to renin, pepsin, cathepsin D, plasmin, tonin or cathepsin G and it is inhibited by pepstatin, but not by diisopropyl fluorophosphate.