The xenobiotic metabolism of 4 in vitro human skin test systems (2D and 3D) was compared with that of the native human skin samples from which the skin test systems had been produced. In total 3 skin samples were investigated, each from a different donor to exclude variability due to gender, donor or tissue supplier. In addition, the skin cultures were compared with a surrogate of the liver. Basal and induced phase I and phase II enzymes were analyzed regarding gene/protein expression as well as enzyme activity. The distinctions between the different test systems and the two dermal compartments (epidermis and dermis) were more noticeable than any donor variability. The 3D models of skin and liver mirrored the in vivo situation more realistically than did the monolayer cultures. Phase I metabolism was more pronounced in the hepatic model, whereas phase II metabolism was more prominent in the reconstructed skin. These results show that reconstructed skin models are a valuable tool for organ-specific safety assessment with regard to xenobiotic metabolism.