We describe three recent patients in whom evaluation of subacute, progressive encephalopathy led to the initial diagnosis of human immunodeficiency virus infection. The clinical neurological picture of a predominance of abnormalities of mental function with few elementary neurological deficits, in conjunction with a paucity of systemic symptoms and lack of evidence for prior opportunistic infections preceding the encephalopathy are notable. The cognitive, behavioral, and neuropsychiatric disturbances are described in detail to illustrate the range of manifestations of disordered mental states associated with encephalopathy in individuals with HIV infection. The importance of a comprehensive and broad-minded work-up by brain magnetic resonance imaging, cerebrospinal fluid examination, and specific microbiological tests in delineating the potential multifactorial pathogenesis of the cerebral syndromes in relation to the HIV infection is emphasized. The gratifying long-term clinical improvements in parallel with resolution of neuroimaging and other laboratory abnormalities in response to antiretroviral drug treatment are reported.