Ultrasound temporally increases skin permeability by altering stratum corneum SC function (sonophoresis). The objective of this study was to evaluate the effect of variable ultrasound conditions on the permeation of diclofenac sodium DS with range of physicochemical properties through EpiDerm™. Permeation studies were carried out in vitro using Franz diffusion cell. HPLC method was used for the determination of the concentration of diclofenac sodium in receiving compartment. Parameters like ultrasound frequency, application time, amplitude, and mode of sonication and distance of ultrasound horn from skin were investigated, and the conditions where the maximum enhancement rate obtained were determined. Application of ultrasound enhanced permeation of diclofenac sodium across EpiDerm™ by fivefolds. The most effective enhancing parameters were power sonication of 20kHz frequency, 20% amplitude at continuous mode for 5min.