We report the first neuropsychological-neuropathological case study of a patient with variant Creutzfeldt-Jakob disease (vCJD) who was seen at the early stages of the disease, and whose cognitive functioning was monitored in the following months until his death. At presentation, his neuropsychological profile included impaired ability to retain new episodic information, deficits on tests of retrieval from semantic memory, and impairments on tests of memory for public knowledge, such as famous personalities. Tests of executive function were also performed poorly. Picture recognition memory and autobiographical memory were relatively spared, as was performance on tests of face perception and complex copying ability. Neuropsychological testing may be useful in monitoring the progression of vCJD, and we provide evidence to show a steady rate of decline in perceptual and naming tasks over a 4-month period. Post-mortem findings showed neuronal loss in the caudate, putamen, dorsal thalamus, cerebellum and occipital cortex. Spongiform changes were found throughout the brain, including the entorhinal cortex and anterior thalamus. Prion protein accumulation was noted in the hippocampus. We hypothesize that primary subcortical damage to structures in the thalamus and neostriatum, together with secondary frontal lobe dysfunction, combine to yield the pattern of neuropsychological impairment and neuropsychological sparing that was found.