1. Studies were directed at determining whether hepatocytes, isolated from female Sprague-Dawley rats, facilitate the uptake of protein-bound long-chain fatty acids. We postulated one form of facilitated uptake may occur through an ionic interaction between the protein-ligand complex and the cell surface. These interactions are expected to supply additional ligand to the cell for uptake. 2. The clearance rate of [3H]-palmitate in the presence of alpha 1-acid-glycoprotein (pI = 2.7), albumin (pI = 4.9) and lysozyme (pI = 11.0) was investigated. Palmitate uptake was determined in the presence of protein concentrations that resulted in similar unbound ligand fractions (= 0.03). The experimental clearance rates were compared to the theoretical predictions based upon the diffusion-reaction model. 3. By use of our experimentally determined equilibrium binding and dissociation rate constants for the various protein-palmitate complexes, the diffusion-reaction model predicted clearance rates were 4.9 microliters s-1/10(6) cells, 4.8 microliters s-1/10(6) cells and 5.5 microliters s-1/10(6) cells for alpha 1-acid-glycoprotein, albumin and lysozyme, respectively; whereas the measured hepatocyte palmitate clearance rates were 1.2 +/- 0.1 microliters s-1/10(6) cells, 2.3 +/- 0.3 microliters s-1/10(6) cells and 7.1 +/- 0.7 microliters s-1/10(6), respectively. 4. Hepatocyte palmitate clearance was significantly faster (P < 0.01) in the presence of lysozyme than albumin which was significantly faster than alpha 1-acid-glycoprotein (P < 0.01). The marked difference in clearance rates could not be explained by considering differences in solution viscosity. 5. Our results are consistent with the notion that ionic interactions between protein-ligand complexes and the cell surface facilitate the ligand uptake by decreasing the diffusional distance of the unbound ligand and/or by facilitating the protein-ligand dissociation rate.