Diphenhydramine hydrochloride (DPH) is an antihistamine used topically to relieve skin itching and, at higher doses, DPH also has the capability to induce local skin anesthesia. The present study investigates the possibility to deliver DPH via iontophoresis using a stainless steel electrode. In-vitro iontophoresis was performed using 1% (w/v) DPH dissolved in glycerin (100%), deionized (DI) water (100%) and a mixture of both (50:50) through porcine ear skin and Franz cell assembly. The applied electrical current was 0, 100, 200, and 300 µA/cm 2 for 60 min. Of the solvents tested, the 100% glycerin provided a consistent increase in DPH skin concentrations with current density and no skin damage. Therefore, the 100% glycerin was selected for in-vivo iontophoresis in a rabbit model at the same three current densities for 60 min. DPH skin concentrations were measured in skin via microdialysis for 240 min. Plasma to skin distribution of DPH was studied following short IVinfusions of 6, 8 and 10 mg/Kg in rabbits. Skin and plasma samples were collected for 420 min. No skin damage was observed even at the higher current density. DPH skin concentrations were higher following iontophoresis than IV-infusion. Thus, iontophoresis of DPH in glycerin from a stainless steel patch may be a safe, effective, and inexpensive way to deliver high dose of DPH topically to the skin.