We have identified two cell subsets in human blood based on the lack of lineage markers (lin-) and the differential expression of immunoglobulin- like transcript receptor 1 (ILT1) and ILT3. One subset (lin-/ILT3+ILT1+) is related to myeloid dendritic cells. The other subset (lin-/ILT3+/ILT1-) corresponds to 'plasmacytoid monocytes'. These cells are found in inflamed lymph nodes in and around the high endothelial venules. They express CD62L and CXCR3, and produce extremely large amounts of type I interferon after stimulation with influenza virus or CD40L. These results, with the distinct cell phenotype, indicate that plasmacytoid monocytes represent a specialized cell lineage that enters inflamed lymph nodes at high endothelial venules, where it produces type I interferon. Plasmacytoid monocytes may protect other cells from viral infections and promote survival of antigen-activated T cells.