A mechanism for the relatively high permeability of vitamin C in relation to the change in the protein domain of the stratum corneum has been proposed. Firstly, the skin permeation characteristics of vitamin C (l-[1-¹⁴C]-ascorbic acid) using whole skin and stripped skin of the hairless mouse were investigated. By employing a double layer model, physicochemical properties such as diffusivity and solubility of vitamin C in each skin layer, stratum corneum and viable skin were determined. Then, the high skin permeation rate of vitamin C was characterized. A differential scanning calorimetry, (DSC), study was employed to investigate the effect of vitamin C on the stratum corneum, a major diffusion barrier for the skin transport of the compound.Vitamin C was found to permeate rapidly through the skin, in spite of its low lipophilicity. The diffusivity determined from the lag-time was approximately 1000 times higher in the stripped skin, compared with whole skin. There is a dramatic increase (10-fold) in the permeation rate in stripped skin indicating the major barrier presented by the stratum corneum to the skin permeation of vitamin C.The DSC profile showed four very distinctive transitions near 100, 128, 135 and 145°C which are associated with protein transitions. Comparing normal skin, the peaks are sharpened and there are additional phase transitions above 90°C. An increase in sharpness reflects an increase in the hydration state of the sample, as hydrogen bonds between H₂O molecules and other hydrogen donating chemicals of skin components become major chemical bonds in hydrated samples. The higher permeation rate of vitamin C observed may be due to its enhancing effect on the hydration capacity of skin and solubilizing action on the protein domain of the stratum corneum.