We compared uptake of palmitate by hepatocyte monolayers with uptake by polyethylene membranes under conditions of identical binding and stirring. Hepatocytes and polyethylene display similar clearances when the fatty acid is free, reflecting partial rate limitation by diffusion across the unstirred water layer. When palmitate is 99.8% bound to albumin, however, hepatocytes clear free fatty acid about seven times faster than does polyethylene. We analyzed the uptake of palmitate by polyethylene at two different pHs to isolate the diffusive resistance of the unstirred layer and to show that codiffusion of bound and free palmitate to the hepatocyte surface accounts for only approximately 20% of the albumin-dependent increment in the clearance of free palmitate. The clearance data are supported by independent measurements of the stagnant layer thickness obtained from indicator dilution data and by an electrochemical method. The findings suggest that hepatocytes facilitate the dissociation of albumin-palmitate complexes. Alternatively, albumin may modulate the uptake capacities of hepatocytes and/or polyethylene.