This study was undertaken to determine the role of scavenger receptor class A type I and II (SR-Al/II) in the physiological scavenger function of hepatic sinusoidal endothelial cells (SEC) and Kupffer cells (KC). Following intravenous administration of radiolabelled SR-ligands, [advanced glycation end (AGE)-products, N-terminal propeptide of type III procollagen (PIIINP) and formaldehyde treated serum albumin (FSA)] in SR-AI/II-deficient and wild-type mice, radioactivity was removed equally rapidly from the circulation of both types of mice. The major site of uptake was the liver. Separation of liver cells showed that the population of SEC and KC were responsible for approximately 55 and approximately 25% of the uptake. There was no difference in plasma clearance, organ distribution or cell distribution in SR-Al/Il-deficient and wild-type mice. Experiments performed to determine the specificity of endocytosis in cultured SEC showed that uptake of radiolabelled SR-ligands (AGE-protein, PIIINP or FSA) was inhibited equally well by unlabelled FSA and AGE-protein in SEC from receptor deficient and wild-type mice. We conclude from these findings that SR-Al/lI is of minor importance in the plasma clearance of physiological as well as foreign SR-ligands.