The purpose of this study was to investigate the effect of delipidization of the stratum corneum (SC) on the in vitro percutaneous absorption of hydrophilic solutes (i.e. water, urea, and inulin). Fourier transform infrared (FT-IR) spectroscopy was employed to study the extent of delipidization of porcine SC due to chloroform:methanol (2:1) (C:M (2:1)) treatments for various time periods. In vitro percutaneous absorption of [ 3 H] water, [ 14 C] urea, and [ 3 H] inulin were studied through C:M (2:1) treated epidermis in Franz diffusion cells. There was a greater decrease in peak areas of the asymmetric and symmetric C–H stretching absorbances (i.e. increase in lipid extraction) with increasing exposure times of the SC with C:M (2:1). After 40-min treatment, asymmetric and symmetric C–H stretching peak area showed a decrease of 75.9 and 89.9%, respectively. The permeability coefficient of water, urea, and inulin increased with increasing lipid extraction. Enhancement in the permeability coefficient, through 40 min C:M (2:1) treated epidermis in comparison to the control, for water, urea, and inulin was 48.72, 215.65, and 3.90, respectively. Log (permeability coefficient) and log (mol. wt.) for test solutes and leuprolide acetate were found to be inversely related (R 2 =0.9974). In conclusion, this study implies that penetration enhancers that are safe and extract the SC lipids can be selected in order to enhance the percutaneous absorption of polar solutes through the skin.