The objectives of this research were (a) to characterize the permselective properties of human and porcine skin and (b) to assess the validity of the latter as a model membrane in iontophoresis studies. The electroosmotic transport of [14C]mannitol was followed in vitro across human and porcine skin as a function of pH, in both "anode-to-cathode" and "cathode-to-anode" directions. At physiological pH, mannitol electrotransport dominated in the anode-to-cathode direction, clearly indicating the net negative charge and the corresponding cation-permselectivity of the skin. By lowering the pH to 3.5 the direction of electroosmosis progressively reverses, indicating that the skin is becoming net positively-charged, and thus anion-selective. The degree of permselectivity (DP) of the skin at each pH value was quantified by dividing mannitol electrotransport in the predominant direction (i.e. either anodal or cathodal) by that in the opposite sense. The net charge on the skin is zero when DP equals unity, corresponding to the isoelectric point (pI) of the membrane (approximately 4.4 for pig skin and approximately 4.8 for human skin). The consistent pIs and similar pH-dependent permselectivities observed for human and pig demonstrate that porcine skin is an appropriate model for iontophoresis studies. Finally, the characterization of the permselective properties of human skin is crucial to optimize the iontophoresis of large peptides and uncharged species, which are transported primarily by electroosmosis.