The range of neuropathology found in cases of prion disease is considerable. The pathology present in dendrites and axons is associated with a marked loss of spines and synaptic contacts. It is probable that this loss underlies the functional and neurological deficits in the disease. Immunocytochemical re-examination of 2 cases of inherited disease with a 144 bp prion gene insertion with no characteristic pathology (i.e. spongiform change, astrocytosis and gliosis), together with 3 typical cases of prion disease (CJD), with antibodies to synaptophysin and synaptic protein demonstrated the presence of synaptic "plaque-like" lesions throughout the temporal cortex and cerebellum. In addition, examining the tissue by image analysis demonstrated a greater than 30% reduction in the relative synaptic index in all the prior disease cases when compared with controls. Synaptic disorganization and/or loss is a fundamental and constant feature of prion disease, irrespective of the presence or absence of spongiform change, neuronal loss and severe gliosis. Assessment of the extent and location of synaptic deficits might produce a more accurate documentation of the degree of neuronal disorganisation occurring during the course of prion disease.