Protozoan parasites of the genus Leishmania exist as obligatory intracellular amastigotes and invade macrophages and Langerhans cells, the dendritic cells of the skin. Langerhans cells are much more efficient in presenting Leishmania major antigen to T cells than macrophages are and have the unique ability to retain parasite antigen in immunogenic form for prolonged periods. To analyze the mechanisms that are responsible for this potency, we defined the synthesis, turnover, conformation, and localization of major histocompatibility complex (MHC) class II molecules in Langerhans cells. Hence, Langerhans cells were pulse-labeled; immunoprecipitation of MHC class II molecules and gel electrophoresis followed. In addition, the subcellular distribution of MHC class II molecules in L. major-infected Langerhans cells was analyzed by confocal microscopy. The results show that (i) newly synthesized MHC class II molecules are required for L. major antigen presentation by Langerhans cells, (ii) MHC class II-peptide complexes in Langerhans cells are long-lived, (iii) phagocytosis of L. major modulates MHC class II biosynthesis by reducing its downregulation during Langerhans cell differentiation, and (iv) newly synthesized MHC class II molecules are associated with the parasitophorous vacuole of infected Langerhans cells. These findings support the conclusion that the traits of MHC class II expression correspond to the highly specialized functions of Langerhans cells in the immunoregulation of cutaneous leishmaniasis.