The histological features of cases of variant Creutzfeldt-Jakob disease (vCJD) are often distributed in the brain in clusters. This study investigated the spatial associations between the clusters of the vacuoles, surviving neurons, and prion protein (PrP) deposits in various brain areas in 11 cases of vCJD. Clusters of vacuoles and surviving neurons were positively correlated in the cerebral cortex but negatively correlated in dentate gyrus. Clusters of the florid and diffuse type of PrP deposit were not positively correlated with those of either the vacuoles or the surviving neurons although a negative correlation was observed between the florid plaques and surviving neurons in some cortical areas. Clusters of florid and diffuse deposits were either negatively correlated or uncorrelated. These data suggest: 10 that clusters of vacuoles in the cerebral cortex are associated with the presence of surviving neuronal cell bodies, 2) that clusters of vacuoles are not spatially related to those of the PrP deposits, and 3) different factors are involved in the pathogenesis of the florid and diffuse PrP deposits.