Huntington disease-like 2 (HDL2) is an autosomal dominant disorder characterized by adult-onset, progressive motor abnormalities, psychiatric disturbances, and dementia ending in premature death. Clinically, it most closely resembles Huntington disease (HD), although a subset of affected individuals have parkinsonian features. Here, we systematically compare 5 HDL2 and 5 HD brains with the hypothesis that, reflecting the clinical presentation, the neuropathology of the 2 diseases would be similar. Gross and microscopic examination revealed prominent striatal neuron loss and astrocytic gliosis in a dorsal to ventral gradient in each disorder and cortical atrophy. Nuclear protein aggregates were as common in HDL2 as in HD, and the ultrastructural features of HDL2 and HD aggregates were similar. Electron microscopy also revealed degenerating neurons, some with evidence of autophagy, in both HDL2 and HD. Small ribonuclear foci, previously associated with potentially neurotoxic RNA transcripts in HDL2, rarely colocalized with protein aggregates in HDL2 brain, although the protein aggregates were stained by anti-TATA-box binding protein antibodies. Overall, the neuropathologic features of HDL2 and HD are very similar but not identical, suggesting that the pathogenetic mechanisms of the 2 diseases may partially overlap.