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.