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Boosted protease inhibitor monotherapy has emerged as an antiretroviral alternative option to avoid the use of nucleosides. After more than seven years of research with hundreds of patients exposed to this kind of therapy, controversy about its use remains. While European and Spanish guidelines for the use of antiretroviral therapy in adults include monotherapy as an alternative for simplification, experts in the USA express the view that this strategy cannot be currently recommended. Our conclusion, after more than seven years of research, is that simplification of a suppressive triple antiretroviral therapy to boosted protease inhibitor monotherapy has demonstrated safety and efficacy in a high proportion of patients. Although this is not a strategy to implement indiscriminately in all patients, it could be a good option for those patients with toxicity related to nucleoside reverse transcriptase inhibitors, or for trying to avoid such toxicities in virologically controlled patients without previous failure to protease inhibitors, restarting nucleosides if the viral load does not remain undetectable. If simplification to monotherapy is selected to treat some patients, twice-daily lopinavir/ritonavir, or preferably once-daily darunavir/ritonavir, should be chosen as data with other boosted protease inhibitors are inconclusive or even nonexistent. Nevertheless, more studies focusing on the control of HIV replication in viral reservoirs with monotherapy, as with triple therapy, are warranted.