Ultrasound and sodium lauryl sulfate (SLS) exhibit a synergistic effect on transdermal transport, when applied simultaneously on the skin. The synergistic mechanism is not fully understood. Previous studies have shown that application of ultrasound simultaneously with SLS, results in enhanced mass transfer and improved penetration and dispersion of the surfactant. In this study we demonstrate that simultaneous application of ultrasound and SLS leads to modification of the pH profile of the stratum corneum. This pH modification within the stratum corneum's microenvironment, can affect both the structure of the lipid layers and the activity of SLS as a chemical enhancer due to its improved lipophilic solubility. The altered pH profile that results in improved SLS lipophilic solubility, together with improved SLS penetration and dispersion, can explain the synergistic enhancing effect of ultrasound and SLS on transdermal transport.