The hepatic and renal retention of indium-111 (111In) from 111In-labeled polypeptides has been the subject of many investigations. Because the lysosome is a common intracellular destination for the degradation of polypeptides, we studied the lysosomal metabolism of 111In-DTPA-labeled glycoproteins targeted to cell surface receptors in vitro and in vivo. We found that 111In-DTPA-glycoproteins were degraded to 111In-DTPA-epsilon-lysine, which was slowly released from cells and recovered intact in urine and feces. These results suggest a mechanism for 111In retention at target and non-target sites.