People with HIV infection have several risk factors for developing neuropsychiatric adverse events: preexisting conditions, HIV disease stage, and antiretroviral treatment. The most widely used system for assessing neuropsychiatric adverse events in clinical trials is the US Division of AIDS severity grading scale, from Grade 1 (mild) to Grade 4 (life-threatening). First-line treatment with efavirenz has been associated with higher rates of neuropsychiatric adverse events than several other antiretrovirals. A MEDLINE search identified 17 randomized clinical trials of first-line HAART with two nucleoside analogs plus efavirenz, of which 13 reported neuropsychiatric adverse events using the Grade 1-4 system. The percentage of patients with graded neuropsychiatric adverse events, and the system used for analysis, was compared across the trials. Of the 13 trials identified, there were five different methods used to report neuropsychiatric adverse events: Grade 1-4 all, Grade 1-4 drug related, Grade 2-4 all, Grade 2-4 drug related, Grade 3-4 all, Grade 3-4 drug related, and adverse events leading to discontinuation. In addition, three trials used questionnaire-based methods instead of the Division of AIDS grading system. There were a significantly higher percentage of patients with Grade 1-4 neurological or psychiatric adverse events in the efavirenz versus comparator arms in the DMP-006, TMC278-C204, and STARTMRK trials. There were generally too few patients with each individual neuropsychiatric adverse event to allow meaningful comparisons of treatment arms. There were no significant differences in Grade 3 or 4 neuropsychiatric adverse events between the treatment arms in the ACTG 5142 or 2NN trials. In summary, there is a wide range of different systems used to report neuropsychiatric adverse events in HIV clinical trials. Use of a standardized endpoint would improve the interpretability of results across clinical trials. (AIDS Rev. 2010;12:67-75) Corresponding author: Andrew Hill, microhaart@aol.com