Tumor necrosis factor (TNF)-alpha has been shown to be increased in brain tissue of AIDS patients and may function as a mediator of cerebral damage. We initiated a study to determine the cellular localization and degree of protein and mRNA expression of the two specific TNF-alpha receptors (TNF-Rs), p55 and p75, in brain tissues from AIDS patients. Cerebral white matter obtained at autopsy from 13 AIDS patients, 10 unhealthy controls, and 4 healthy controls was evaluated. Double-label immunohistochemistry revealed prominent up-regulation of p55 and p75 TNF-Rs on activated macrophages and microglial cells in all AIDS patients; no increased staining was found on astrocytes. Staining was most prominent in patients with opportunistic infection of the brain and in microglial nodules of patients with HIV encephalitis. Brain tissues also showed increased expression of interleukin (IL)-1 beta, IL-6, and TNF-alpha, cytokines known to up-regulate the TNF-Rs. Increased staining for TNF-Rs was also found in patients with multiple sclerosis, chronic cerebral edema, and radiation necrosis but not in an asymptomatic HIV-positive patient without AIDS. Reverse transcriptase polymerase chain reaction performed on adjacent sections from five AIDS patients revealed up-regulation from normal for p55 in all patients and for p75 in three patients. The up-regulation of both TNF-Rs in AIDS suggests that macrophages and microglial cells may be important in amplifying the TNF-alpha response.