The evolution of central nervous system (CNS) impairments associated with human immunodeficiency virus (HIV) infection was assessed by a prospective, longitudinal study of patients in a methadone maintenance clinic. At a mean of 47 months after baseline testing, which included physical exams, HIV antibody testing and a neuropsychological (NP) screening battery, 121 subjects received a second NP assessment. Forty subjects (33%) who were seropositive at baseline showed statistically significant declines in NP function over the 4 years compared with 81 seronegatives, on the Finger Tapping and Trail Making B tests. This relatively long-term follow-up suggests that subtle cognitive deficits develop over time and can be identified early, but their course is slow and appears generally to parallel that of non-CNS symptoms/signs of HIV infection.