Abstract: Type 1 diabetes (T1D) is a T cell-mediated disease. Various DC populations play important roles in initiating and directing T cell responses and thus may be critical for T1D pathogenesis. We thus examined peripheral blood DC1 and DC2 populations by flow cytometry in healthy controls, subjects at risk for T1D, new-onset patients, and established T1D patients. We found a significant increase in the number of DCs (including DC1 and DC2) in at-risk subjects and those with new-onset T1D versus healthy controls and established T1D patients (ANOVA; p < 0.0001). Analysis of DC1 and DC2 subsets in these same groups demonstrated a significant decrease in the ratio of DC1 and DC2 in subjects at risk and new-onset and established T1D patients in contrast with healthy controls (p < 0.0001). Both subsets of peripheral blood DCs from T1D patients expressed significantly higher levels of HLA-DR than healthy controls. Peripheral blood mononuclear cells from T1D patients secreted significantly higher amounts of IFN-α than controls, and IFN-α production correlated inversely with the DC1/DC2 ratio. This study demonstrates a marked increase in peripheral blood DC numbers that occurs during a time of active autoimmunity in at-risk subjects and patients with new-onset T1D, but is lost in established diabetes. However, the abnormal distribution of peripheral blood DC populations appears to be a persistent phenotype in all stages of T1D.