Purpose: To find out about the long-term safety and efficacy of nonnucleoside reverse transcriptase inhibitors (NNRTIs) within the central nervous system (CNS) in the context of reports suggesting a higher incidence of severe neuropsychiatric disorders resulting from HIV treatment with efavirenz (EFV). Method: Retrospective analysis of a large cohort with regular neuropsychiatric follow-up. We compared 414 patients on EFV and 320 on nevirapine (NVP) with regard to CD4 cell count, HIV plasma viral burden, CNS dysfunction described by psychomotor speed, HIV dementia scale, neuropsychological tests assessing memory and attention, selfreported psychiatric and somatic complaints, depression, and psychosis. Results: No significant differences between both types of NNRTI treatment regimens were found with regard to duration of therapy and reasons for withdrawal: virological failure, neurological failure, and neuropsychiatric side effects including the manifestation of depression, psychosis, insomnia, or other self-reported complaints. Conclusion: The present data do not provide evidence for a higher incidence of light and/or severe neuropsychiatric side effects associated with NNRTI treatment.