Neuronal loss in the cerebral cortex in Huntington's disease (HD) has not been well documented, nor has its laminar pattern been definitively established. We therefore counted neurons in individual cortical laminae in the dorsal frontal cortex of 5 HD and 5 control autopsy brains. Significant neuronal loss (to 57% of control, P = 0.002) was found in layer VI of HD brains. These cells project principally to the thalamus, the claustrum and other regions of cerebral cortex; thus their loss is unlikely to be the result of retrograde degeneration secondary to striatal pathology. Layer V neurons were also decreased (to 71% of control, P = 0.034). Degeneration of cerebral cortical neurons may be at least partly responsible for some of the non-choreic symptoms of HD, such as dementia, irritability, apathy, and depression.