The distinctive synaptic degenerative changes induced by congenital hydrocephalus, brain trauma and brain tumors are reviewed. The hydrocephalic or interstitial clear edema, the hematogenous edema fluid in traumatic brain injuries, and the proteinaceous edema fluid in brain tumors accumulated in the dilated extracellular space of cerebral cortex neuropil induce swelling and shrinkage of pre- and postsynaptic structures, increased amount of presynaptic axoplasmic granular substance, and clumping, enlargement and depletion of synaptic vesicles. In most human cases examined, the clear and dark types of degeneration are observed in both pre and/or postsynaptic structures. Filamentous hypertrophy of presynaptic endings also is observed in some cases. Osmiophylic bodies, necrotic membranes, lipid inclusions and glycogen granules are seen in the synaptic terminal matrix. Disappearance of synaptic densities is evident in some cases. In severe brain edema, swollen and shrunken presynaptic endings with discontinuous limiting plasma appear separated from the postsynaptic structures and detached from the glial ensheathment expressing synaptic disassembly. Phagocytosis of isolated presynaptic endings, and of the entire synaptic contacts by astrocytes, microglial cells, and by non-nervous invading cells, such as monocytes and macrophages, are frequently observed. The biochemical events underlying synaptic degeneration and the neurodegenerative diseases exhibiting synaptic degeneration are analyzed.