longterm efavirenz use is associated with worse neurocognitive functioning in hivinfected patients neurocognitive nc complications continue to afflict a substantial proportion of hivinfected people taking effective antiretroviral therapy art one contributing mechanism for this is antiretroviral neurotoxicity efavirenz efv is associated with shortterm central nervous system cns toxicity but less is known about its longterm effects our objective was to compare nc functioning with longterm use of efv to that of a comparator lopinavirritonavir lpvr in a cohort of wellcharacterized adults four hundred fortyfive patients were selected from the cns hiv antiretroviral therapy effects research charter cohort based on their use of either efv n272 mean duration 179 months or lpvr n173 mean duration 164 months and the lack of severe nc comorbidities all patients had undergone standardized comprehensive nc testing univariable and multivariable analyses to predict nc outcomes were performed compared with lpvr users efv users were more likely to be taking their first art regimen p0001 were less likely to have aids p0001 or hepatitis c virus hcv coinfection p005 had higher cd4 t cell nadirs p0001 had lower peak p0001 and current p0001 plasma hiv rna levels and were less likely to have detectable hiv rna in cerebrospinal fluid csf p0001 overall efv users had worse speed of information processing p004 verbal fluency p003 and working memory p003 an interaction with hcv serostatus was present overall among hcv seronegatives n329 efv users performed poorly whereas among hcv seropositives n116 lpvr users had overall worse performance in the subgroup with undetectable plasma hiv rna n269 efv users had worse speed of information processing p002 and executive functioning p003 substantial differences exist between efv and lpvr users in this observational cohort possibly because of channeling by clinicians who may have prescribed lpvr to more severely ill patients or as secondline therapy despite these differences efv users had worse functioning in several cognitive abilities a potentially important interaction was identified that could indicate that the nc consequences of specific antiretroviral drugs may differ based on hcv coinfection the complexity of these data is substantial and findings would best be confirmed in a randomized clinical trial