The diffusion of acetazolamide from buffered saline and buffered albumin solutions into human erythrocytes has been characterized. A model was developed for describing the effects of both intra- and extracellular binding on the approach to distributional equilibrium. Unbound acetazolamide entered the cells via an apparent first-order process at a rate that was unaffected by salicylate at a therapeutic concentration of 200 micrograms/mL. Salicylate concentrations ranging from approximately 100 to 400 micrograms/mL, were, however, extremely effective in displacing acetazolamide from its serum protein binding sites. Free fractions of acetazolamide in human serum were found to increase by an order of magnitude as salicylate concentrations approached 400 micrograms/mL, thereby greatly increasing the concentration of unbound drug available for passive diffusion into cells. The results indicate that while competitive binding effects, which may alter unbound drug concentration-time profiles and potentially impact on toxicity, do occur, alterations in red cell membrane permeability, which could adversely affect carbon dioxide transport, are not of significance.