The mechanism of renal handling of angiotensin II was studied in vivo in the renal circulation of the intact anesthetized dog and in vitro in whole blood using 14C 5 Ile angiotensin II, l Asp 125I angiotensin II, and d Asp 125I angiotensin II. 75% of a 600 pmole bolus of 14C angiotensin II was degraded in a single passage through the kidney as measured by radioactive tracer and radioimmunoassay techniques. The metabolic products were 14C 5 Ile (59%), 5 Ile 8 Phe (15%), and 3 Val 8 Phe (2%); recovery of the injected radioactive material was 99%. The degradation rate of 14C angiotensin II in whole dog blood in vitro was only 17%/min. Similar metabolic patterns were seen in vivo and in vitro. 66% of the injected l Asp 125I angiotensin II was metabolized, but only 23% of the d Asp 125I angiotensin II was metabolized in a single passage through the kidney. These observations indicate that, under the conditions of these experiments: angiotensin II is rapidly metabolized in the dog kidney by multiple enzymes, including an aminopeptidase; circulating plasma enzymes do not account for the renal handling of angiotensin II; and angiotensin II is not sequestered in the kidney.