Ionic copper entering the blood plasma binds tightly to albumin and the macroglobulin, transcuprein. It then goes primarily to the liver and kidney, except in lactation where a large portion goes directly to the mammary gland. Little is known about how this copper is taken up from these plasma proteins. To examine this, kinetics of uptake from purified human albumin and ₂-macroglobulin, and effects of inhibitors, were measured using human hepatic (HepG2) and mammary epithelial (PMC42) cell lines. At physiological concentrations (3-6µM) both cell types took up copper from these proteins independently and at rates similar to each other and to those for Cu-histidine or Cu-nitrilotriacetate (NTA). Uptakes from ₂-macroglobulin indicated a single saturable system in each cell type, but with different kinetics, and 65-80% inhibition by Ag(I) in the HepG2 but not PMC42 cells. Uptake kinetics for Cu-albumin were more complex and also differed with cell type (also for Cu-histidine and NTA); and there was little or no inhibition by Ag(I). High Fe(II) concentrations (100-500 µM) inhibited copper uptake from albumin 20-30% in both cell types, that from ₂-macroglobulin 0-30% and with no inhibition of the latter by Mn(II) or Zn(II). We conclude that the proteins mainly responsible for the plasma exchangeable copper pool deliver the metal to mammalian cells efficiently and by several different mechanisms. ₂-Macroglobulin delivers it primarily to CTR1 in hepatic but not mammary epithelial cells; and additional as yet unidentified copper transporters or systems for uptake from these proteins remain to be identified.