Despite the rapidly increasing incidence of HIV infection worldwide and the increasing prevalence of HIVassociated cognitive impairment, even in patients adequately treated with antiretroviral therapy, currently no effective treatment exists for HIV dementia. A broad range of studies using either brain or cerebrospinal fluid (CSF) tissues from well-characterized patients with HIV dementia, animal models, and in vitro studies from several laboratories using HIV-infected cells or HIV proteins provide overwhelming evidence for oxidative stress in mediating neuronal injury in this patient population. These studies also suggest that patients with apolipoprotein E (ApoE) 4 allele are more susceptible to such oxidative damage. In this review, we provide a critical analysis of these studies, including the few clinical trials that have used antioxidants to treat HIV dementia. We also discuss several novel agents with potent antioxidative properties and provide a rationale for combination antioxidant and neuroprotective therapy.