Plasma clearance of intact and desialylated rat and human transcortin after iv injection into rats and hamsters has been investigated. Intact rat transcortin was shown to have an approximately 5-fold longer half-life in the rat circulation than human transcortin. Removal of sialic acid residues resulted in a reduction of the half-life of rat transcortin from 4 h to 90 sec. This rapid clearance could be blocked by simultaneous injection of asialofetuin, but the clearance of intact rat transcortin was unaffected by asialofetuin. Five rat organs (pancreas, uterus, kidney, liver, and psoas muscle) were sampled at 30 and 60 min after injection of iodinated rat or human transcortin and examined for their intact transcortin levels relative to those of plasma and [14C]sucrose distribution volumes. With the exception of the liver, the organs had lower tissue:plasma ratios of [125I]iodo-transcortin than did [14C]sucrose. Liver was found to accumulate 3--8 times more human [125I]iodo-transcortin than rat [125I]iodo-transcortin, suggesting that this organ plays a greater role in the degradation and plasma clearance of human transcortin. When injected into hamsters, rat and human transcortin both had relatively long half-lives (5.8 and 6.8 h, respectively), which were dramatically shortened when sialic acid was removed. Our results suggest that the differences observed in the half-lives of these two species of transcortin in the rat are most likely due to differences in the metabolism of these two transcortins by the endogenous neuraminidase(s).