The recent discovery that adrenalectomy results in hippocampal granule cell loss suggested that this phenomenon might be useful as a model of selective, experimentally controlled neuronal death possibly relevant to neurodegenerative disorders. This study was designed to provide a detailed qualitative anatomical description of the phenomenon and to determine whether adrenalectomy-induced dentate granule cell degeneration constitutes a reliable model of selective neuronal death. Silver impregnation staining revealed that granule cell degeneration begins immediately after adrenalectomy and continues for months in both sexes, in young and older adults, and in all strains tested. In one group of 77 adrenalectomized rats, 82% exhibited silver-impregnated granule cells. This phenomenon is extraordinarily selective in that no neurons other than dentate granule cells degenerated after adrenalectomy. There was considerable variability among animals in the number of cells degenerating at a given time-point or in the degree of ultimate cell loss. In the most extreme cases, virtually complete granule cell loss was present throughout approximately 80% of the dentate gyrus. Nissl staining revealed that degenerating granule cells exhibited coalescing of nuclear chromatin into multiple nuclear bodies and pyknosis without accompanying glial swelling. This morphology is distinct from the necrosis caused by other neurotoxic insults and is the subject of the ultrastructural companion paper identifying this type of cell death as apoptosis. Taken together, these results indicate that adrenalectomy reliably initiates an immediate, highly selective, and long-continuing process of hippocampal granule cell degeneration that exhibits morphological features characteristic of apoptosis, rather than necrosis. The possibility that this apoptotic cell death involves a biochemical cascade relevant to programmed cell death and/or neurodegenerative diseases suggests that this model may be valuable for studies of neuronal death and its prevention. Some practical guidelines for use of this model are described.