Progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), sporadic multisystem tauopathy, and some forms of frontotemporal dementia with Parkinsonism linked to chromosome 17 are characterized by neuronal and glial lesions accumulating tau protein containing 4 conserved repeats in microtubule-binding domain (4R tau). Corticospinal tract degeneration is not a common feature of 4R tauopathies. Our objective was to describe 12 cases with pathologic features similar to those of PSP but with prominent corticospinal tract degeneration. We reviewed the historical records and neuropathologic evaluation using standardized sampling, immunohistochemistry, semiquantitative analysis, image analysis, and electron microscopy. The mean age at onset and illness duration was 71 and 5.7 years, respectively. Eight cases were female. Eleven cases had clinical evidence of prominent upper motor neuron disease plus extrapyramidal features. There was focal parasagittal cortical atrophy involving motor cortex and degeneration of corticospinal tract with sparing of lower motor neurons like in primary lateral sclerosis. Prominent tau pathology was found in oligodendrocytes in motor cortex, subjacent white matter, and corticospinal tract characterized by globular cytoplasmic filamentous inclusions that were immunoreactive for 4R tau. The clinicopathologic features of these 12 cases expand the spectrum of 4R tauopathies.