The liver harbors a diversity of cell types that have been reported to stimulate T cells. Although most hepatic dendritic cells are immature, a small population of CD11c^high conventional dendritic cells (cDCs) exists that expresses high levels of costimulatory molecules. We sought to determine the relative contribution of cDCs to cross‐presentation by the liver. In vitro, liver nonparenchymal cells (NPCs) depleted of cDCs induced only minimal proliferation and activation of antigen‐specific CD8⁺ T cells when loaded with soluble protein antigen. Using a transgenic mouse with the CD11c promoter driving expression of the human diphtheria toxin receptor, we found that selective depletion of cDCs in vivo reduced the number and activation of antigen‐specific CD8⁺ T cells in the liver after intravenous administration of soluble protein antigen. Adoptive transfer of DCs, but not CD40 stimulation, restored the hepatic T‐cell response. Conclusion: Our findings indicate that the ability of the liver to effectively cross‐present soluble protein to antigen‐specific CD8⁺ T cells depends primarily on cDCs. Despite costimulation, other resident liver antigen‐presenting cells cannot compensate for the absence of cDCs. (HEPATOLOGY 2008.)