Antigen cross‐presentation is a principal function of specialized antigen‐presenting cells of bone marrow origin such as dendritic cells. Although these cells are sometimes known as “professional” antigen‐presenting cells, nonbone marrow‐derived cells may also act as antigen‐presenting cells. Here, using four‐way liver cell isolation and parallel comparison of candidate antigen‐presenting cells, we show that, depending on the abundance of antigen‐donor cells, different subsets of liver cells could cross‐present a hepatocyte‐associated antigen. This function was observed in both liver sinusoidal endothelial cells and Kupffer cells even at very low antigen concentration, as well as when using soluble protein. Antigen cross‐presentation by liver cells induced efficient CD8+ T‐cell proliferation in a similar manner to classical dendritic cells from spleen. However, proliferated cells expressed a lower level of T‐cell activation markers and intracellular interferon‐gamma levels. In contrast to classical spleen dendritic cells, cross‐presentation by liver antigen‐presenting cells was predominantly dependent on intercellular adhesion molecule‐1. Conclusion: Hepatic sinusoids are an environment rich in antigen cross‐presenting activity. However, the liver's resident antigen‐presenting cells cause partial T‐cell activation. These results clarify how the liver can act as a primary site of CD8+ T‐cell activation, and why immunity against hepatocyte pathogens is sometimes ineffective. (HEPATOLOGY 2011;54:1379–1387)