Treatment of HIV-1 infections with nevirapine is associated with skin and liver toxicity. These two organ toxicities range from mild to severe, in rare cases resulting in life-threatening liver failure or toxic epidermal necrolysis. The study of the mechanistic steps leading to nevirapine-induced skin rash has been facilitated by the discovery of an animal model in which nevirapine causes a skin rash in rats that closely mimics the rash reported in patients. The similarity in characteristics of the rash between humans and rats strongly suggests that the basic mechanism is the same in both. The rash is clearly immune-mediated in rats, and partial depletion of CD4(+) T cells, but not CD8(+) T cells, is protective. We have demonstrated that the rash is related to the 12-hydroxylation of nevirapine rather than to the parent drug. This is presumably because the 12-hydroxy metabolite can be converted to a reactive quinone methide in skin, but that remains to be demonstrated. Although the rash is clearly related to the 12-hydroxy metabolite rather than the parent drug, cells from rechallenged animals respond ex vivo to the parent drug by producing cytokines such as interferon-gamma with little response to the 12-hydroxy metabolite, even when the rash was induced by treatment with the metabolite rather than the parent drug. This indicates that the response of T cells in vitro cannot be used to determine what caused an immune response. We are now studying the detailed steps by which the 12-hydroxy metabolite induces an immune response and skin rash. This animal model provides a unique tool to study the mechanistic details of an idiosyncratic drug reaction; however, it is likely that there are significant differences in the mechanisms of different idiosyncratic drug reactions, and therefore the results of these studies cannot safely be generalized to all idiosyncratic drug reactions.