PURPOSE: To delineate the contributions of electrorepulsion and electroosmosis to the iontophoretic flux of 5-FU across porcine skin in vitro. Also, the isoelectric point (pI) of the skin model was determined. METHODS: The electrotransport of 5-FU, anode-to-cathode ("anodal") and cathode-to-anode ("cathodal") was determined as a function of the pH of the electrolyte bathing the skin. RESULTS: At pH 8.5, the drug (pKa approximately 8) is negatively charged and "cathodal", viz. electrorepulsive, transport is much greater than that in the opposite direction. At pH 7.4, where approximately 25% of 5-FU is charged, electrorepulsive and electroosmotic ("anodal") fluxes are balanced. Decreasing the pH to 6, and then 5, reduces the percentage of ionized 5-FU such that "anodal" electroosmosis dominates across the negatively-charged membrane. But, at pH 4, "anodal" and "cathodal" fluxes are again equal suggesting neutralization of the skin (i.e., pI approximately 4). This is confirmed at pH 3, where "cathodal" electroosmosis dominates across the now net-positively charged barrier. CONCLUSIONS: Electrotransport is sensitive, mechanistically, to the properties of the permeant and of the skin; interactions of, for example, the drug or constituents of a formulation, that alter the barrier's net charge, can affect iontophoretic delivery. The pI of porcine ear skin is approximately 4.