Darunavir/ritonavir monotherapy is an experimental switching strategy for virologically suppressed patients without protease inhibitor resistance to avoid nucleos(t)ide-related toxicities. This therapy maintains virological suppression in most patients, but at slightly lower rates than standard therapy that includes two nucleos(t)ides. Patients experiencing virological failure are generally re-suppressed without emergence of resistance with the resumption of two nucleos(t)ides. Reports of cerebrospinal fluid viral escape has been observed in patients receiving protease inhibitor monotherapy, and concerns exist regarding the capacity of protease inhibitor monotherapy to control HIV infection in the brain and to prevent neurocognitive decline. In the current report we have pooled together available evidence regarding the capacity of darunavir/ritonavir monotherapy to control HIV replication in cerebrospinal fluid and to prevent neurocognitive decline.