Blockade of the retrograde axonal transport of isthmo-optic nucleus (ION) neurons in the avian embryo results in their massive degeneration. We used this system to investigate the response of macrophage/microglial cells to neuronal degeneration in the embryonic brain. Colchicine was injected into the right eye of quail or chick embryos at a time when the survival of ION neurons depends on retrograde trophic support from the retina, and the chronology of the subsequent macrophage/microglial response in the ION was analyzed. This response was restricted to the ION contralateral to the injected eye; no modifications of the normal state were observed in the surrounding parenchyma or in the opposite ION, used as control. The response was first detected 18 hours after the colchicine injection (18 hours pi), when an increase of the macrophage/microglial cell number was evident. The number of these cells in the affected ION increased, peaking at 40-48 hours pi. At later survival times, macrophage/microglial cells were progressively less abundant in the affected ION, which gradually diminished in size. At 120 hours pi the only remnant of the ION was a small cluster of macrophage/microglial cells, surrounded by a clear area with scarce nonmicroglial cells, in the region formerly occupied by the ION. This study reveals that a strong macrophage/microglial response occurs in the embryonic brain in response to neuronal degeneration but that these cells do not trigger the neuronal death, as they only appear after pyknotic fragments are already observable.