Highly active antiretroviral therapy plays a central role in the development of lipodystrophy syndrome, which may affect up to 50% of patients depending on the diagnostic criteria used. Most protease inhibitors and nucleoside reverse transcriptase inhibitors (NRTIs) are involved in body fat changes and associated metabolic disturbances. In contrast, non-NRTIs have not been directly related to the onset of this syndrome. One of the most widely used methods to evaluate body fat changes is dual-energy X-ray absorptiometry (DEXA), which can detect differences in the distribution of body fat in patients with and without lipodystrophy. New information from a randomized open-label clinical trial suggests that efavirenz could have greater potential for causing lipoatrophy than lopinavir+ritonavir. This paper examines the impact of efavirenz on adipose tissue and body fat composition in order to evaluate whether this drug plays a role in the development of lipodystrophy. We have focused on the evidence obtained from comparative randomized clinical trials that use an objective measurement of fat distribution, such as DEXA. We analysed available in vitro data and evidence from non-comparative clinical trials.