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Central nervous system (CNS) adverse events are common with initiation of efavirenz, but these are often described as transient. We aimed to describe the outcomes of individuals commencing Atripla (Gilead Sciences Inc, Foster City, California; Bristol-Myers Squibb Co, Princeton, New Jersey, USA) as a first-line regimen.We performed a retrospective case-based analysis of all individuals within our HIV cohort who had received Atripla as their first antiretroviral combination. In individuals who discontinued Atripla data was collected on evolution of adverse events.Four hundred and seventy-two individuals commenced Atripla as first-line therapy at 12 months, 383 individuals (81%) remained on Atripla with 98% achieving HIV-1 RNA less than 50 copies/ml (on treatment analysis). CNS toxicity was the commonest reason for switching therapy in 63 (71%) cases. The median duration of first reported CNS toxicity was 27 days (IQR 7–104 days) and the commonest reported symptoms were nightmares or vivid dreams in 28 (44%), insomnia in 27 (43%) and depression in 22 (35%). In those with CNS toxicity, six (10%) switched at 0–4 weeks, four (6%) at 4–12 weeks, 30 (48%) at 12–52 weeks and 23 (36%) changed regimen 52–96 weeks after commencing Atripla. Among those with available documentation 25 of 63 (40%) had reported improvement or resolution of their CNS side effects.One-fifth of all individuals commencing Atripla will need to switch therapy, often for adverse events. The commonest reason for switch in our cohort was CNS toxicity, which although it may develop shortly after initiation may persist, ultimately leading to discontinuation of Atripla months or years later.