Previous studies have shown that plasma transcobalamin II (TCII) facilitates the cellular uptake of [57Co] vitamin B12 (B12) by a variety of tissues, but the lack of an intrinsic label on the protein moiety of the TCII-B12 complex has made it impossible to determine the role and fate of TCII during this process. We have labeled homogensous rabbit and human TCII with 125I-labeled N-succinimidyl-3-(4-hydroxyphenyl) propionate and have performed in vivo experiments in rabbits. When 125I-labeled rabbit TCII-[57Co] B12 and 131I-labeled bovine albumin were simultaneously injected intravenously, we observed that 125Iand 57Co were cleared from plasma at a faster rate (t1/2 = 1 1/2 h) than 131I and that 125I and 57Co were present in excess of 131I in the kidney, liver, spleen, heart, lung, and small intestine 1/2 h after injection. Later, 57Co remained in excess of 131I, but the ratio of 125I to 131I decreased progressively in all of these plasma and were rapidly excreted in the urine. After 1 h following injection, 57Co was present in excess of 125I in the plasma...