Abstract Intravenous injection of 125I-radiolabeled submaxillary gland renin into mice resulted in rapid disappearance of this protein with a corresponding increase in its metabolites in the serum. The disappearance rate was substantially reduced after nephrectomy. Result from the in vitro incubation of the labeled renin with the whole blood excluded the possibility of any blood components participating in renin degradation. During the in vivo study, the kidneys were found to accumulate fivefold to sevenfold more radioactivity than the liver. The degradation of the labeled renin by the kidney and the liver was studied in vitro in slice preparations after preloading of the protein into organs in vivo for 15 min. Formation of metabolites was followed by the determination of the trichloroacetic acid-soluble radioactivity. Results from these in vitro experiments suggested that both tissues had about the same capacities to degrade the accumulated renin. A substantial amount of this renin-degradation activity could be inhibited by the metabolic energy inhibitors, sodium azide and 2,4-dinitrophenol, and the lysosomal inhibitor, chloroquine. The lysosomal localization of the organ-accumulated renin after subcellular fractionation further implied the active internalization of the protein into lysosomes. Although the efficiency for renin degradation by both types of tissue were about the same, the in vivo uptake of labeled renin by the kidneys surpassed the uptake by the liver by severalfold. It is concluded that the kidneys play a major role in the degradation of circulating submaxillary gland renin.