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Structured antiretroviral treatment interruption (STI) has been advocated as a therapeutic strategy for HIV-1 infection. We report initial observations of cerebrospinal fluid (CSF) HIV-1 infection in five patients undergoing serial lumbar punctures (LPs) during STI undertaken following virological failure.In this prospective observational study we quantified HIV-1 RNA concentrations and assessed both phenotypic drug susceptibility profiles and genotypic antiviral drug resistance mutations in CSF and plasma during the period of treatment interruption. CSF white blood cells were also counted, and patients’ neurological status monitored.In four of the patients, CSF HIV-1 concentration increased more rapidly than that of the plasma, with consequent reduction in the ratio between plasma and CSF viral loads (pVL : cVL). Three individuals developed robust, though asymptomatic CSF lymphocytic pleocytosis. In all patients the predominant HIV-1 quasispecies shifted simultaneously in CSF and plasma from a drug-resistant to a more drug-susceptible phenotype with identical and simultaneous changes in genotypes associated with drug resistance.STI may be accompanied by previously unrecognized changes in tissue viral exposures and lymphocyte traffic. Hence, despite ‘virological failure’ as evidenced by persistent plasma viremia, ongoing antiretroviral treatment prior to its interruption appeared to suppress CSF HIV-1 infection (indeed more effectively than that of plasma) and restrain lymphocyte traffic into the CSF. Simultaneous change of resistance mutations in CSF and plasma was likely due to re-emergence and overgrowth of pre-existing strains with ready exchange of virus between these two compartments, either facilitated by or provoking a local CSF lymphocytosis.