Efavirenz is widely used as part of combination antiretroviral therapy in HIV-infected patients. Central nervous system adverse effects are the most important reason for discontinuation of this drug. A recent combined analysis of phase III data showed a two-fold increased risk of suicidal ideation or suicide attempts, when compared with non-efavirenz-containing regimens. This commentary discusses the data from this analysis, tries to explain these observations and the implications for clinical practice, and puts them into perspective in relation to efavirenz's prominent position as a first-line drug for the treatment of HIV infection.