HIV infection often results in MRI-detectable brain atrophy and white matter signal hyperintensities (WMSHs). Magnetic resonance images were obtained from 31 HIV+ male patients and 10 high-risk controls. Variation within the HIV+ group on neuropsychological (NP) impairment and stage of systemic disease were relatively independent, allowing examination of the relative association of MRI measures with NP impairment versus with systemic stage of disease. HIV+ patients compared to high-risk controls evidenced global atrophy, reduced caudate nuclei volume, and a trend to gray matter volume loss but no difference in white matter volume or in WMSHs. These effects were progressive with CDC clinical stage such that patients at CDC stage A had values very close to those of controls, while patients at CDC stage C had the most abnormal values. In contrast, the relationship between these MRI variables and severity of NP impairment was much less dramatic, with the mildly to moderately impaired HIV+ subjects showing MRI volume effects greater than or equal to those of the severely impaired HIV+ subjects. These results suggest that MRI-detectable brain atrophy secondary to HIV infection is not the primary substrate underlying the progressive NP impairment in HIV disease.