HIV-1 enters the central nervous system by passing the blood-brain barrier during primary infection. Despite the introduction of combination antiretroviral therapy, the prevalence of HIV-associated neurocognitive disorders remains high and is probably related to ongoing viral neuropathological processes. The central nervous system forms a distinct physiological, cellular, and pharmacological environment. We aimed to systematically review whether the central nervous system also constitutes a distinct virological compartment, allowing differential genotypic evolution of HIV-1. Only original research papers that compared paired plasma/cerebrospinal fluid samples for drug resistance associated mutations as defined by the IAS-USA Drug Resistance Mutations Panel or compared viral envelope (env) patterns or coreceptor prediction were included. If available, HIV RNA levels were included in the analysis, with a relevant difference defined as 0.5 log10 copies/ml. Data from 35 reports with heterogeneous study design and methods was pooled and statistical analysis was performed as appropriate. A total of 555 subjects with 671 samples could be included in this review. We observed that compartmentalization of the central nervous system occurs frequently as reflected by differences in HIV viral load, resistance associated mutations, and viral coreceptor tropism preference.