Autoimmune diseases are often associated with microbial infections. Molecular mimicry between microbial antigens and self‐epitopes has been suggested as a mechanism for breaking self‐toleranceand induction of autoimmunity. Since infections also cause inflammatory responses we explored the role of local inflammation in organ‐specific autoimmunity. For this purpose, transgenic mice were used expressing the MHC class I molecule K^b exclusively on hepatocytes. These mice exhibit K^b‐specific tolerance as exemplified by the acceptance of K^b+ grafts. Inflammatory reactions were induced by injection of immunostimulatory cytosine‐phosphorothioate‐guanine (CpG)‐rich oligodeoxynucleotides (ODN). Application of CpG‐ODN is sufficient to break tolerance in vivo, and to cause activation of K^b‐specific CD8⁺ T cells and subsequent autoaggression against hepatocytes. The CpG‐ODN‐induced inflammation appears to have two major effects. First, it causes infiltration of T cells into the liver parenchyma. Second, adhesion and costimulatory molecules are up‐regulated on hepatocytes so that the infiltrating CD8⁺ T cells encounter K^b on hepatocytes, which display an APC‐like phenotype, resulting in activation and tissue damage. Autoimmune hepatitis can be maintained for at least eight weeks by repeated application of CpG‐ODN but subsides after termination of the inflammatory stimulus, suggesting the requirement of additional factors for a self‐perpetuation of autoimmunity. These observations describe an additional pathway for the induction of autoimmunity, i.e. in the absence of microbial antigens inflammatory reactions alone can lead to infiltration of T cells into organs, resulting in breaking of tolerance and autoaggression. Moreover, the results provide evidence that T cell activation can take place not only in draining lymph nodes but also directly on parenchymal cells.