Several matrix and adhesion molecules in fish optic nerve, which are constitutively expressed, are increased during axonal regeneration and are primarily associated with nonneuronal cells (W.P. Battisti, Y. Shinar, M. Schwartz, P. Levitt, and M. Murray [1992] J. Neurocytol. 21:557-573). The current study examines the reactions of specific cell types to optic nerve crush and axonal regeneration. The goldfish optic nerve contains macroglia and microglia as well as a population of monocyte-derived cells (granular macrophages) unique to goldfish. Two cell types were OX-42 positive (granular macrophages and microglia), indicating monocyte lineage, each with a distinct morphology and distribution within the nerve. Within hours of the optic nerve crush, the number of OX-42-labeled cell profiles increased near the crush site, remained elevated during the time axons were elongating, and then declined. Microglia, but not granular macrophages, were phagocytically active. Astrocytes are readily identified in the normal optic nerve, but they exhibited marked morphologic changes within hours of injury, which is consistent with the contribution these cells make to the altered environment. Oligodendroglia could not be reliably identified in regenerating optic nerves until myelin was formed. A comparison of the distribution of OX-42-labeled cells with that of transforming growth factor beta-1 (TGF-beta 1) and tenascin suggests that these molecules are expressed by granular macrophages. Tenascin staining may be additionally associated with astrocytes and/or microglia. The rapid response of these nonneuronal cells to injury, their rapid phagocytic activity, and the secretion of growth-promoting factors by these cells likely contributes to the environment that supports robust regeneration by optic axons in the goldfish.