Brain region specificity is a feature characteristic of neurodegenerative disorders, such as Huntington's disease (HD). We have studied the brain region-specific vulnerability of striatal compared with cortical and mesencephalic astrocytes treated with 3-nitropropionic acid (NPA), an in vitro model of HD. Mitochondrial dysfunction is involved in neurodegenerative processes. We have previously demonstrated a causal relationship between NPA-induced transcription of the cytochrome c oxidase (COX) subunit IV isoform (cox4i2) and increased oxidative stress leading to higher rates of necrotic cell death in striatal astrocytes by the application of a small interfering RNA knockdown system. Here, we have investigated the correlation of COX IV-2 protein expression with intracellular ATP content, mitochondrial peroxide production, and viability of astrocytes from three different brain regions. In cortical and mesencephalic astrocytes, NPA caused an elevation of cox4i2 transcription as in striatal astroglia. However, increased COX IV-2 and decreased COX IV-1 protein expression levels have been observed only in striatal astrocytes. In agreement with our hypothesis, Striatal astrocytes showed the highest levels of peroxide production and necrotic cell death rates compared with cortical and mesencephalic astroglia. Thus, we suggest that the higher vulnerability of astrocytes from the striatum in our in vitro model of HD is, at least in part, based on brain region-specific differences of the COX IV-2/COX IV-1 protein ratios and accompanied elevated oxidative stress.