Genetic polymorphisms in the regulatory regions of various cytokine genes influence the amount of cytokine produced in response to inflammatory stimuli. To determine whether such polymorphisms might play a role in human immunodeficiency virus (HIV) dementia, a disease process in which tumor necrosis factor (TNF)-α is believed to play a role, we analyzed HIV-infected adults with and without dementia and control populations for a polymorphic site located in the promoter region of the gene coding for TNF-α. The presence of the A allele at the TNF-α-308 site was overrepresented among adults with HIV dementia compared to those without dementia (0.28 versus 0.07; OR 5.5; 95% CI 1.8–17.0) and a healthy control population (0.28 versus 0.11). The increased frequency of the A allele in HIV-infected adults with dementia suggests that this locus may play a role in the pathophysiology of dementia and suggests a genetic predisposition for the development of HIV dementia.