Circulating myeloid cells such as plasmacytoid dendritic cells (pDC), blood DC and monocytes act as blood sentinels detecting invading pathogens through a large repertoire of expression of toll-like receptors (TLRs). Activation of these receptors is crucial to detect invading pathogens by the innate immune system. In the present work, we analysed the TLR responsiveness of fibrocytes, a blood-derived cell type of myeloid origin. Fibrocytes efficiently responded to TLR2, TLR4, and TLR7 ligands as well as to poly (I:C) or viral stimulation by producing high amount of interleukin-6. Upon virus infection of fibrocytes, IFN type I was also induced. When compared to pDC or Flt3 ligand-derived DC, fibrocytes produced 5 times and 60 times more IL-6, respectively. This response was associated with a rapid and efficient translocation of the NF-kappaB transcription factor. Analysis of the expression and functionality of TLR7 in peripheral blood leukocyte subpopulations suggested that this receptor is expressed and functional in a CD163(+) monocytic cell subpopulation containing the fibrocyte precursors. Considering the rapid entry of fibrocytes into wounds, this efficient responsiveness to TLR danger signals, reflects a potentially important role of these cells in the first line of defence against pathogen invasion following traumata.