Patients with human immunodeficiency virus (HIV) could present with a variety of diseases that affect the central nervous system. The introduction of highly active antiretroviral therapy and the evolution of radiological and laboratory findings play an important role in acquired immunodeficiency syndrome management. Nevertheless, in cases of failure of noninvasive diagnostic algorithms, brain biopsy can be performed as the investigational procedure of the last resort. This work reports a review of the literature on this debated argument and underlines the impact of brain biopsy on the management of HIV patients.