After intravenous injection of a low dose (25 µg/kg) in rats, the anti HIV-1 compound succinylated human serum albumin (Suc-HSA) is taken up mainly in the liver and spleen and is proteolytically degraded. Ten minutes after injection of 125I-Suc-HSA, 72 and 14% of the dose were found in the liver and spleen, respectively. With immunohistochemistry we demonstrated that in both organs, Suc-HSA was specifically endocytosed in endothelial cells. In the isolated perfused rat liver preparation, liver uptake was shown to be saturable, with a Km of 2.9 10−8M and a Vmax of 2.4 µg/inin/100 g body weight. The apparent Km and Vmaxin vivo were 2.2 10−7M and 10.3 µg/min/100 g, respectively. Uptake in liver and spleen was inhibited by preadministration of an excess of formaldehyde-treated albumin and with polyinosinic acid, indicating the involvement of the scavenger receptor, as anticipated for such polyanionic compounds. Suc-HSA is not absorbed intact from the colon and the ileum. After injecting (i.v.) rats with a high dose of Suc-HSA (10 mg/kg), the elimination t½ was 3 hr, and therefore, sustained plasma levels above the concentration needed for in vitro anti-HIV-1 activity can be achieved.