To detect the earliest structural changes in the brain in human immunodeficiency virus (HIV) infection, 118 gay men and 115 parenteral drug users enrolled in a study of the natural history of HIV infection underwent magnetic resonance imaging evaluations. Routine T2-weighted and heavily T2-weighted scans for quantification of brain water were obtained, blinded to HIV serostatus. Atrophy and foci of increased signal did not correlate with any medical, immunologic, neurologic, or neuropsychologic parameters in the group as a whole, or in the gay men or parenteral drug user subgroups. Three subjects had progressive multifocal leukoencephalopathy and one had central nervous system lymphoma. In a subgroup in whom intracranial water percent was calculated, correlations were found with CD4 counts and CD4/CD8 ratios. We conclude that standard magnetic resonance imaging of the brain does not differentiate asymptomatic and mildly symptomatic HIV-positive individuals from HIV-negative individuals, regardless of risk group. However, intracranial water percent may distinguish HIV-positive from HIV-negative individuals because it correlates with raw CD4 counts and CD4/CD8 ratios.