AbstractReactive microgliosis is a highly characteristic response to neural injury and disease, which may influence neurodegenerative processes and neural plasticity. We have investigated the origin and characteristics of reactive microglia in the acute phase of their activation in the dentate gyrus following transection of the entorhino‐dentate perforant path projection. To investigate the possible link between microglia and hematopoietic precursors, we analyzed the expression of the stem cell marker CD34 by lesion‐reactive microglia in conjunction with the proliferation marker bromodeoxyuridine (BrdU) and the use of radiation bone marrow (BM) chimeric mice. We found that CD34 is upregulated on early‐activated resident microglia, rather than by infiltrating bone marrow‐derived cells. The number of CD34+ microglia peaked at day 3 when 67% of the resident CD11b/Mac‐1+ microglia co‐expressed CD34, and all CD34+ cells co‐expressed Mac‐1, and decreased sharply toward day 5, unlike Mac‐1, which was maximally expressed at day 5. Approximately 80% of the CD34+ cells in the denervated dentate gyrus had incorporated BrdU into their nuclei at day 3. We also showed that CD34 is upregulated on early‐activated microglia in the facial motor nucleus following peripheral axotomy. The results suggest lesion‐reactive microglia to consist of functionally distinct subpopulations of cells; a major population of activated resident CD34+Mac‐1+ microglia with a high capacity for self‐renewal, and a subpopulation of CD34−Mac‐1+ microglia which has a mixed extrinsic and intrinsic origin and whose proliferative capacity is unknown. © 2005 Wiley‐Liss, Inc.