The concentration-dependent effects of sodium dodecyl sulfate (SDS) on the in vitro permeability of the buccal mucosa were assessed using caffeine (CAF) and estradiol (E 2 ) as model hydrophilic and lipophilic markers, respectively. The permeability of CAF and E 2 through porcine buccal mucosa was determined in modified Ussing chambers, with and without exposure to different concentrations of SDS (0.01, 0.05, 0.1, and 1% w/v in physiological buffer). Permeability experiments were complemented with light microscopic evaluation of untreated and SDS-treated tissues. Additionally, the critical micellar concentration of SDS in the physiological buffer and the effect of SDS pretreatment on drug solubility were determined. Pretreatment of buccal mucosa with SDS 0.01% had no effect on CAF or E 2 permeability. SDS 0.05, 0.1, and 1% significantly enhanced CAF flux by a factor of 1.57, 1.63, and 1.81, respectively, and caused significant removal of superficial cells, as observed with light microscopy. Interestingly, pretreatment with SDS 0.05% did not affect E 2 flux, whereas SDS at !0.1% significantly reduced E 2 permeability, possibly as a result of micellar solubilization. These results demonstrate that the effect of SDS on buccal permeability depends on both the concentration of SDS used and the physicochemical properties of the permeant.