Changes in motor cortical activation are associated with the major symptoms observed in both Parkinson's disease and progressive supranuclear palsy (PSP). While research has concentrated on basal ganglia abnormalities as central to these cortical changes, several studies in both disorders have shown pathology in the thalamus and motor cortices. In particular, we recently reported an 88% loss of corticocortical projection neurones in the pre-supplementary motor (pre-SMA) cortex in Parkinson's disease. Further analysis of the degree of neuronal loss and pathology in motor cortices and their thalamocortical relays in Parkinson's disease and PSP is warranted. Six cases with PSP, nine cases with Parkinson's disease and nine controls were selected from a prospectively studied brain donor cohort. alpha-Synuclein, ubiquitin and tau immunohistochemistry were used to identify pathological lesions. Unbiased stereological methods were used to analyse atrophy and neuronal loss in the motor thalamus [ventral anterior, ventrolateral anterior and ventrolateral posterior (VLp) nuclei] and motor cortices (primary motor, dorsolateral premotor and pre-SMA cortices). Analysis of variance and post hoc testing was used to determine differences between groups. In Parkinson's disease, the motor thalamus and motor cortices (apart from the pre-SMA) were preserved containing only rare alpha-synuclein-positive and ubiquitin-positive Lewy bodies. In contrast, patients with PSP had significant atrophy and neuronal loss in VLp (22 and 30%, respectively), pre-SMA (21 and 51%, respectively) and primary motor cortices (33 and 54%, respectively). In the primary motor cortex of PSP cases, neuronal loss was confined to inhibitory interneurones, whereas in the pre-SMA both interneurones (reduced by 26%) and corticocortical projection neurones (reduced by 82%) were affected. Tau-positive neurofibrillary and glial tangles were observed throughout the motor thalamus and motor cortices in PSP. These non-dopaminergic lesions in motor circuits are likely to contribute to the pathogenesis of both PSP and Parkinson's disease. The selective involvement of the VLp and primary motor cortex in PSP implicates these cerebellothalamocortical pathways as differentiating this disease, possibly contributing to the early falls.