Mometasone furoate (MF) is a potent steroid for treatment of e.g., eczema and psoriasis. It exerts its function by binding to the glucocorticoid receptors in viable epidermis and dermis. The aim of the current project was to estimate if two clinically equivalent 0.1% MF creams, one w/o (A) and one o/w (B) cream, might impose different systemic load, which is related to adverse side effects. We approached this question by combining analysis of drug permeability in flow through cells and membrane perturbation detected by impedance spectroscopy using excised porcine skin as membranes. We also analyzed the amount of drug that accumulates in the membranes following topical application of the two creams. The results show that both creams generate about the same amount of MF in skin, while cream A generates an order of magnitude higher drug flux through skin. Cream A also caused a twofold increase in the skin dielectric constant (ε), which may be attributed to an increased fluidity of the extracellular lipid matrix in the stratum corneum corresponding to a higher skin permeability. No significant change in skin ε was seen with cream B. To conclude, cream B appears to be the safer alternative as it does not seem to perturb the skin and imposes less systemic burden without sacrificing clinical efficacy