Psychomotor slowing predicts the development of HIV-1-associated dementia, AIDS, and death independent of immune status. We retrospectively selected all patients who showed pathologic psychomotor slowing as a sign of central nervous system (CNS) dysfunction before the onset of therapy and who were then treated with nonnucleoside reverse-transcriptase inhibitors-either efavirenz (EFV) (n = 65 patients) or nevirapine (NVP) (n = 39 patients), each given in combination with two nucleoside analogues (NAs). Patients who were treated only with two NAs (n = 66) served as controls. Patients were observed for 6 months. Both EFV and NVP combinations improved CNS function as determined by electrophysiologic motor tests. The therapeutic effects of EFV and NVP did not depend on the type of NA added. Although results did not reach significance, NVP combinations were more effective than EFV combinations or therapy regimens with NAs alone in patients who were naïve to all antiretroviral therapy. EFV and NVP combinations were equally effective in patients pretreated with highly active antiretroviral therapy, including protease inhibitors.