Reticuloendothelial system phagocytosis was evaluated in vivo by the clearance and tissue distribution of 99mTc-albumin millimicrospheres in rats. Administration of i.p. silica 2 days prior to clearance measurement increased the half-life of millimicrospheres 24% compared with control animals (P less than 0.01). Impairment of phagocytic activity was maintained at 5 days to 22% over control values (P less than 0.01). Tissue distribution studies showed that liver uptake was reduced and splenic and pulmonary uptake was increased compared with control. Cyclosporine i.v. increased half-life by 14% 1 hr after administration )P = NS) and half-life returned to control values by 8 hr. Hepatosplenic shift was less marked than after silica treatment. Phospholipid liposomes i.v. produced prompt impairment of millimicrosphere clearance after 1 hr; half-life was prolonged 46% over control values (P less than 0.001 vs. control) and marked radiolabel shift to the spleen and lung was seen. Measurements done 18 hr after a dose of liposomes revealed an increase of 55% over control half-life (P less than 0.001). Liposomes appear to be potent, nontoxic--and, in some cases, reversible agents--for blockade of reticuloendothelial phagocytosis and examination of non-phagocytic reticuloendothelial functions. These results help to explain some of the results obtained in pancreatic islet grafting and suggest that phospholipid liposomes may be useful in this form of transplantation.