We report a case of an HIV-infected patient who was successfully treated with ritonavir/lopinavir (r/LPV) monotherapy for several years. He presented with neurological symptoms and high HIV RNA levels in cerebrospinal fluid (CSF). Sequencing of the HIV from the CSF revealed mutations in the protease gene reflecting resistance against most protease inhibitors, that is, lopinavir and ritonavir. His regimen was switched and after 2 months the HIV RNA viral load was again undetectable in both plasma as well as in CSF. Monotherapy with r/LPV may not be sufficient to fully suppress viral replication in the central nervous system in all individuals and may lead to compartimentalization and the selection of resistant mutations of HIV in the central nervous system.