Iontophoresis is believed to have great added value for the delivery of drugs to the systemic circulation via the transdermal route. Whether iontophoretic transdermal systems can be applied for a wide variety of drugs, will at the same time depend on the intrinsic safety of current application to the skin. We investigated the effect of electric current in vivo on human skin by measuring two different aspects of the irritant response: (a) the effect on the stratum corneum barrier function by measuring transepidermal water loss (TEWL); (b) effects at the level of the dermal vascular bed by measuring the erythematous response with Laser Doppler Flowmetry (LDF). Nine volunteers entered the study. DC (direct constant current) profiles were applied to the volar forearms of the subjects for 30 min. Following the application of DC and pulsed DC current profiles, TEWL and LDF measurements were carried out on these sites, on so-called passive control sites (occluded by the application chamber containing the buffer solution, but without applying current) and on untreated sites. TEWL values measured directly after patch removal were 1.5-2.0 times higher than the baseline values for TEWL regardless the presence or absence of electric current. The effect of the electric current application on the TEWL followed the same relaxation profile as the effect of buffer application without current. The erythematous response however did differ significantly from the controls. The response on the anodal sites was 1.5–2.7 times higher than at the cathodal sites. The erythema lasted from 25 to 69 min. The time span for relaxation of the erythema was independent of the current profile (DC vs. pulsed DC) but was longer at the anodal sites than at the cathodal sites. It was concluded from this study that after a single current application the effect on the barrier to water loss is negligible because the effect on TEWL cannot be distinguished from the occlusive effect resulting from the application of the aqueous buffer alone, without current. The erythematous response to current application was relatively moderate and dependent on current direction.