The objective of this study was to quantify the acute effects of iontophoretic current passage on human skin in vivo. Specifically, local skin blood flow (SBF) and transepidermal water loss (TEWL) have been measured at the sites of electrode application before and subsequent to iontophoresis at current levels which are generally considered to be ‘reasonable'. Infrared spectra were also recorded at the same skin sites using the attenuated total reflectance technique (ATR-IR). The current levels administered were up to 0.5 mA/cm2 for a maximum of 25 min. It was found that current application for only 5 min was sufficient to cause a significant increase in SBF. Longer periods of current flow induced greater changes in SBF, the elevated level of which persisted for longer times after the termination of iontophoresis. Typically, SBF increased more beneath the anode than beneath the cathode, although visually the degree of irritation was sometimes difficult to distinguish. All subjects were able to feel the application of current, the majority registering greater discomfort at the anode. Apart from the occlusive effect of the electrode chamber solutions, iontophoresis elicited no significant change in TEWL relative to the no-current controls. Similarly, ATR-IR detected no major changes in the spectroscopic profile of the outer stratum corneum. Only relatively minor alterations in protein conformational distribution were observed. In summary, the acute effects of iontophoresis on human skin in vivo are quite moderate. The most significant effect is the rather consistent induction of an erythematous response, the persistence of which depends upon the quantity of charge and the absolute level of current delivered.