Islets of Langerhans from normal mice contained dendritic cells (DCs) in the range of 8-10 per islet. DCs were found in several mouse strains, including those from lymphocyte-deficient mice. DCs were absent in islets from colony stimulating factor-1 deficient mice and this absence correlated with small size islets. Most DCs were found next to blood vessels and resided in islets for several days. Some DCs contained insulin-like granules, and most expressed peptide-MHC complexes derived from beta cell proteins. Islet DCs were highly effective in presenting beta cell antigens to CD4 T cells ex vivo. Presentation of beta cell-derived peptide-MHC complexes by DCs neither depended on islet inflammation nor correlated with the extent of spontaneous beta cell death. Periislet stroma DCs did not contain beta cell peptide-MHC complexes; however, 50% of DCs in pancreatic node were positive. Hence, presentation of high levels of beta cell antigens normally takes place by islet DCs, a finding that has to be placed in the perspective of autoimmune diabetes.