The fate of the circulating C-terminal propeptide of type I procollagen (PICP) was studied. Trace amounts of 125I-PICP administered intravenously to rats disappeared from the blood with an initial t1/2 of 6.1 min. After 45 min the radioactivity was distributed as follows: liver, 36%; blood, 23%; kidneys, 18%; urine, 20%; spleen, 1%; lungs, 2%; heart, 0.4%. To prevent escape of label from the site of uptake, PICP was labelled with 125I-tyramine cellobiose (125I-TC), which is trapped intralysosomally. With this ligand a serum t1/2 of 8.7 min was recorded, and 70% and 20% was traced in the liver and kidneys respectively. The uptake per liver endothelial cell (LEC) was 1000 times that per parenchymal cell and twice that per Kupffer cell. At 1 h and 6 h after addition of 125I-PICP to cultured LEC, 15% and 45% respectively, had been endocytosed. Only ligands for the mannose receptor could compete with PICP for endocytosis. To study whether the same specificity was operative in vivo, 125I-PICP was injected along with an excess of ovalbumin, which is known to be endocytosed by the mannose receptor of LEC. The serum t1/2 was prolonged from 6 to 16 min, signifying that terminal mannose residues are an important signal for clearance of PICP. In conclusion, these studies show that LEC constitute the main site of uptake of circulating PICP. The uptake is mediated by endocytic receptors which recognize terminal mannose residues.