AbstractThe retina contains two distinct populations of monocyte‐derived cells: perivascular cells (macrophages) and parenchymal cells (microglia), important in homeostasis, neuroinflammation, degeneration, and injury. The turnover of these cells in the retina and their repopulation in normal physiological conditions have not been clarified. Bone marrow (BM) cells from EGFP‐transgenic mice were adoptively transferred into lethally irradiated normal adult C57BL/6 mice. Eight, 14, and 26 weeks later mice were sacrificed and retinal flatmounts were prepared. Retinal microglia were identified by F4/80, CD45, and Iba‐1 immunostaining. BrdU was injected into normal mice for 3–14 days and cell proliferation was examined by confocal microscopy of retinal flatmounts. Few (6.15 ± 2.02 cells/retina) BrdU+ cells were detected and of these some coexpressed CD11b (1.67 ± 0.62 cells/retina) or F4/80 (0.57 ± 0.30 cells/retina). BM‐derived EGFP+ cells were detected by 8‐weeks post‐transplantation. By 6 months, all retinal myeloid cells were EGFP+. Consecutively, donor BM‐EGFP+ cells were demonstrated within the: (1) peripheral and juxtapapillary retina, (2) ganglion cell layer, (3) inner and outer plexiform layers, and (4) photoreceptor layer. EGFP+ cells within the ganglion layer were amoeboid in shape and F4/80highCD45highIba‐1high, whereas cells in the inner and outer plexiform layers were ramified and F4/80low CD45lowIba‐1low. Perivascular macrophages expressed less F4/80, CD45, and Iba‐1 compared with parenchymal microglia. Our results suggest that BM‐derived monocyte precursor cells are able to migrate across the BRB and replace retinal microglia/macrophages. The complete replacement of retinal microglia/macrophages takes about 6 months. In situ proliferation was predominantly of nonhemopoetic retinal cells. © 2007 Wiley‐Liss, Inc.