Mitochondria play an essential role in cellular energy production and calcium homeostasis. Abnormalities in mitochondrial homeostasis and function are seen in several acquired as well as genetic neuropathies, emphasizing their prominent role in neuronal cell activities. Chronic infection with HIV, even when appropriately treated, is a risk factor for developing peripheral neuropathy. In this chapter, we discuss the way in which HIV infection, the resultant toxic viral products that are generated, and some of the viral inhibitors used in its treatment may lead to abnormal mitochondrial function. Of importance are the effects on mitochondrial DNA replication and the neurotoxic effects of the viral gp120 protein. One aspect of mitochondrial dysfunction that remains unexplored is the role of the interaction between mitochondria and the endoplasmic reticulum as a possible target of disruption in HIV neuropathy.