To characterize the natural history of autologous epidural blood patch (EBP) in human immunodeficiency virus (HIV)-seropositive patients, records from an ongoing longitudinal study of the neuropsychological manifestations of HIV infection were retrospectively reviewed. Of 252 participants (218 HIV-seropositive, 34 HIV-seronegative) who underwent at least one diagnostic lumbar puncture, 9 (7 seropositive, 2 seronegative) required EBP for post-dural puncture headache. After EBP, 6 of the seropositive subjects underwent serial neuropsychological evaluations over periods ranging from 6 to 24 months; none of these six subjects had a decline in neurocognitive performance or other adverse neurologic or infectious sequelae. We were unable to identify morbidity attributable to EBP in the HIV-seropositive patient followed for as long as 2 yr.