Peripheral tolerance is considered to be a safeguard against autoimmunity. Using a TCR‐transgenic mouse system displaying peripheral tolerance against a liver‐specific MHC class I K^b antigen, we investigated whether the breaking of tolerance would result in autoimmunity. Reversal of tolerance was achieved by simultaneous challenge with cells expressing the K^b autoantigen and IL‐2. Tolerance could not be broken with IL‐2 alone or when K^b‐ and IL‐2‐expressing cells were applied to different sites of the mice. However, despite the presence of activated autoreactive T cells that were able to reject K^b‐positive grafts no autoaggression against the K^b‐positive liver was observed. These results indicate that breaking of tolerance per se is not sufficient to cause liver‐specific autoimmunity. However, when in addition to breaking tolerance the mice were infected with a liver‐specific pathogen, autoaggression occurred. Thus, in this system at least two independent steps seem to be required for organ‐specific autoimmunity: reversal of peripheral tolerance resulting in functional activation of autoreactive T cells and conditioning of the liver microenvironment which enables the activated T cells to cause tissue damage.