To gain a better understanding of the interaction of the model detergent sodium lauryl sulfate (SLS) with the stratum corneum, we investigated systematically the ultrastructural changes of the epidermal barrier and the nucleated parts of the epidermis after the occluded application of different concentrations of SLS in human. Different application models were investigated. Two of the three irritation procedures (long duration exposure and the repetitive exposure for 3 d) provoked damage of the nucleated parts of the epidermis and alterations of the lower parts of the stratum corneum. Here, the extrusion and transformation of lamellar body derived lipids into lamellar lipid bilayers were disturbed; however, the upper portions of stratum corneum displayed intact intercellular lipid layers that contradict the long-standing belief that surfactants damage the skin by delipidization. Furthermore, we investigated ultrastructurally and by measurement of transepidermal water loss the influence and protective capacity of a lipophilic barrier cream on acute irritant contact dermatitis. The irritant contact dermatitis was induced by the standardized cumulative short application model with two SLS concentrations (0.5% and 0.75%). The cumulative type of exposure simulates daily living more realistically. Because most of the previous tests have been performed on the human forearm or back, we analyzed whether the pattern of response was similar on both sites. The back showed a higher level of irritant reaction, but the pattern of irritant response proved to be similar to the forearm. Application of the barrier cream before and during irritation showed a decrease of transepidermal water loss enhancement with 0.5% SLS by 58% (back) and 49% (arm) and after irritation with 0.75% SLS by 56% (back) and 43% (arm). Because the experimental result correlated with the clinical experience, the development of the cumulative short exposure model might help to predict and to discriminate the efficacy of barrier creams.