The adrenal gland of the mouse exhibits uptake mechanisms for plasma high density lipoprotein (HDL) and low density lipoprotein (LDL). To study this uptake, we lowered the endogenous plasma lipoprotein level in mice by administering 4-aminopyrazolopyrimidine and then injected the animals with tracer amounts of human 125 I-HDL or 125 I-LDL intravenously. Uptake of 125 I-HDL and 125 I-LDL in the adrenal gland was demonstrable within 2 min after injection, and the content of radioactivity reached a steady state within 30 min. The adrenal gland accumulated 20-fold more 125 I radioactivity/mg of tissue than lung or kidney. Moreover, the adrenal took up 50-to 200-fold more 125 I-HDL or 125 I-LDL than 125 I-albumin. Adrenal uptake of both lipoproteins was reduced when adrenocorticotrophic hormone secretion was suppressed by dexamethasone. Uptake of either LDL or HDL raised the level of cholesteryl esters in the adrenal gland and suppressed the activity of microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase. The uptake mechanisms were saturable in that unlabeled lipoproteins competed with the 125 I-lipoproteins for uptake. In cross-competition experiments, unlabeled LDL competed more effectively than unlabeled HDL for 125 I-LDL uptake; conversely, unlabeled HDL competed more effectively than unlabeled LDL for 125 I-HDL uptake. These data suggest that two different lipoprotein uptake systems supply cholesterol to the adrenal gland of the mouse, one using LDL and another using HDL.