The properties of the cell types that are selectively vulnerable in Huntington’s disease (HD) cortex, the nature of somatic CAG expansions of mHTT in these cells, and their importance in CNS circuitry have not been delineated. Here, we employed serial fluorescence-activated nuclear sorting (sFANS), deep molecular profiling, and single-nucleus RNA sequencing (snRNA-seq) of motor-cortex samples from thirteen predominantly early stage, clinically diagnosed HD donors and selected samples from cingulate, visual, insular, and prefrontal cortices to demonstrate loss of layer 5a pyramidal neurons in HD. Extensive mHTT CAG expansions occur in vulnerable layer 5a pyramidal cells, and in Betz cells, layers 6a and 6b neurons that are resilient in HD. Retrograde tracing experiments in macaque brains identify layer 5a neurons as corticostriatal pyramidal cells. We propose that enhanced somatic mHTT CAG expansion and altered synaptic function act together to cause corticostriatal disconnection and selective neuronal vulnerability in HD cerebral cortex. Display omitted •sFANS molecular profiling of cell types in Huntington’s disease cerebral cortex•Loss of L5a corticostriatal projection neurons in Huntington’s disease•Extensive somatic CAG expansion occurs in vulnerable and resilient neurons•Gene expression analyses indicate altered synaptic function in layers 5 and 6 neurons Vulnerable cell types in the cerebral cortex in Huntington’s disease have not been delineated completely. Pressl et al. employed sFANS and snRNA-seq to reveal that L5a corticostriatal pyramidal cells are lost early in HD progression. Molecular profiling data implicate somatic CAG expansion and altered synaptic function in HD pathogenesis.