Extracellular proteins are not generally presented on class I MHC molecules in vitro, yet many studies show that a pathway exists in vivo for the presentation of extracellular material on class I molecules to prime CD8+ T cell responses. Here, we provide morphological evidence that proteins taken up by macropinocytosis can gain access to the cytosol and therefore into the conventional class I MHC pathway. Class I presentation of soluble ovalbumin by mouse bone marrow macrophages was dramatically enhanced by MCSF or phorbol ester and blocked by amiloride, which stimulate and inhibit membrane ruffling and macropinocytosis, respectively. Brefeldin A, gelonin, and a peptide aldehyde inhibitor of proteasomal processing each blocked presentation of macropinocytosed antigen, demonstrating that unusual access to the conventional class I MHC pathway was occurring. This novel cell type-specific endocytic pathway may facilitate presentation of exogenous material on class I MHC molecules, allowing induction of CD8+ T cell responses to soluble proteins, tumor cell fragments, and some pathogens.