The response of T cells to liver Ags sometimes results in immune tolerance. This has been proposed to result from local, intrahepatic priming, while the expression of the same Ag in liver-draining lymph nodes is believed to result in effective immunity. We tested this model, using an exogenous model Ag expressed only in hepatocytes, due to infection with an adeno-associated virus vector. T cell activation was exclusively intrahepatic, yet in contrast to the predictions of the current model, this resulted in clonal expansion, IFN-γ synthesis, and cytotoxic effector function. Local activation of naive CD8+ T cells can therefore cause full CD8+ T cell activation, and hepatocellular presentation cannot be used to explain the failure of CTL effector function against some liver pathogens such as hepatitis C.