Retinoids, a class of polyisoprenoids including retinol and retinoic acid, regulate and control diverse physiological functions via their cell-differentiating and morphogenic potential. In the present study we showed that the extracellular concentration of retinoid-binding proteins such as albumin limits the amount of retinoid entering the human promyelocytic leukemia cell line HL-60. These cells accumulate 5 -10 times more retinoid when delivered free in solution than when bound to either albumin or low-density lipoprotein (LDL). Moreover. the effect of protein binding is concentration-dependent, with a higher concentration of binding protein corresponding to a lower level of cellular uptake. Furthermore, the uptake of the ester derivative is higher than that of the acidic retinoid. These observations suggest that (a) the cellular uptake of both retinoids occurs via the free form of the ligand in solution, with the free concentration of ligand decreasing as the carrier-protein concentration increases, and (b) according to a passive mechanism, the ester derivative, unionized and lipophilic, enters the cells more easily than does the acidic derivative.