Multiple sclerosis (MS) and AIDS dementia complex (ADC), also termed HIV-associated dementia (HAD), are two examples of CNS diseases with a strong inflammatory component. In particular, macrophage/microglia activation in the deep white matter (DWM) is a key feature of both diseases. Activated macrophages/microglia have been shown to produce multiple cellular substances which can cause injury and apoptosis to all cell types in the CNS. This potentially provides a link between the initial pathogenic event and subsequent widespread neuroaxonal injury, which recent studies have found to be an early finding and an important determinant of clinical burden in both diseases. This review summarizes important immunopathological and neurobiological aspects of MS and ADC, with a special focus on the relation between macrophage/microglia activation and neuroaxonal injury, and discusses potential neuroprotective strategies.