We prospectively studied a cohort of 25 HIV-1 infected individuals with no clinical signs of encephalopathy with 99mTc-HMPAO-SPECT. The findings were correlated with magnetic resonance imaging (MRI), neuropsychological testing and clinical staging aiming at the early diagnosis of HIV encephalopathy by single photon emission computed tomography (SPECT). A total of 25 matched seronegative controls were subject to neuropsychological testing only. A total of 24 patients and controls were monitored for 6-46 months (mean and median 26 months). No patients developed AIDS dementia complex during the study; 3 patients developed minimal symptoms (MSK classification stage 0.5). There was a significant decline in 99mTc-HMPAO uptake over time and neuropsychological abnormalities progressed. Unexpectedly, there was a correlation of high cortical and subcortical 99mTc-HMPAO uptake and low performance in cognitive dysfunction tests, indicating a possible inflammatory reaction in the brain with increased blood flow due to HIV infection. We conclude that, in non-demented HIV-infected individuals, both the 99mTc-HMPAO uptake and functional level slowly decrease over time, but the regional cerebral blood flow decrease could be masked by a direct HIV-induced inflammatory reaction in the brain, which gives a 99mTc-HMPAO hyperfixation.