SummaryBackground:Keratolytics are often used to accelerate and improve the therapeutic response of hyperkeratotic dermatoses. Keratolytics are a chemically inhomogeneous group of substances and substance mixtures that clinically lead to a decrease in symptoms of a cornification disorder, but mediate different effects. Thus, keratolytic, keratoplastic, keratoemulsifying and keratodiluting effects are distinguished. The physicochemical effects or pharmacological efficacy of the respective keratolytics result in different mechanism as well as risks with regard to local or systemic compatibility. Until now, only little attention has been paid upon selection of keratolytics to the immediate consequences regarding diffusion conditions and pharmacokinetics of sequentially applied topicals, in particular of glucocorticoids.Patients and Methods:This paper deals with the influence of keratolytics on the penetration‐time profile of betamethasone dipropionate in sequential application. For this purpose, cutaneous bioavailability was investigated with the Franz chamber test using a tritium‐labeled drug depending on the previous application of a keratolytic agent. Comparative data analyses were performed.Results:It was shown that keratoplastic substances significantly promote diffusion of the glucocorticoid. Keratoemulsifying substance mixtures exert no relevant effects in this regard, while keratodiluting substance mixtures inhibit penetration.Conclusions:The targeted selection of a keratolytic can optimize the therapeutic effect and influence the bioavailability of sequentially applied topicals.