The plasma clearance kinetics of the amyloid-related high density lipoprotein (HDL) apoprotein serum amyloid protein (apoSAA) was examined in BALB/c mice by two different methods, using labeled 125I-apoSAA-rich HDL and unlabeled plasma apoSAA (clearance monitored by radioimmunoassay). The plasma half-life of apoSAA, estimated by both methods, was on the order of 75-80 min, as compared with a value of approximately 11 h for mouse apoA-I. In trace-labeling studies, the rapid plasma clearance of both major 125I-labeled apoSAA isotypes was observed; this metabolic behavior was unique to these polypeptides among HDL apoproteins. The property of rapid plasma clearance was lost upon purification and reconstitution of 125I-apoSAA with HDL, indicating that this property is labile to denaturing conditions. Studies aimed at determining the metabolic fate of 125I-apoSAA gave no evidence for either the selective excretion of 125I-apoSAA or clearance to unique tissue sites as compared with other 125I-HDL apoproteins.