Despite the clinical benefit observed with early highly active antiretroviral therapy, its toxicity and inconvenience, and the strategy of sequentially adding newly available drugs to failing regimens meant that for many patients, it was difficult to build an effective regimen soon after starting therapy. In this setting, the idea of using double-boosted protease inhibitors (PIs) to build a potent regimen emerged. The rationale for the simultaneous use of two PIs is (i) to provide synergistic or additive activity against HIV; (ii) to achieve higher plasma concentrations of both PIs with only one booster; (iii) to increase the genetic barrier to resistance; and/or (iv) to avoid toxicity with nucleoside reverse transcriptase inhibitor-sparing regimens.Double-boosted PI strategies are not recommended in treatment-naive patients because of their low success rate and the availability of more convenient and effective regimens.There are no adequate trials in treatment-experienced patients to establish the clinical efficacy of double-boosted PI regimens; however, the published non-comparative studies suggest considerable efficacy with certain combinations (e.g. lopinavir/ritonavir plus atazanavir, lopinavir/ritonavir plus saquinavir and others) in patients in whom a conventional regimen with one boosted PI could have little chance of success.New drugs of old and new classes that are better tolerated and have different resistance profiles have become available in recent years. These drugs have demonstrated their efficacy in randomized clinical trials, even in patients with extensive treatment experience and high drug resistance. Nowadays, in almost all patients, it is possible to elaborate a regimen with three active drugs, achieving success rates similar to those obtained in treatment-naive patients with recommended regimens. In this context, it is unthinkable that double-boosted PIs could play any role.Double-boosted PIs may be an alternative for those patients with limited therapeutic options in resource-poor settings, where new expensive drugs are not currently available. The fixed combination of lopinavir/ritonavir tablets makes it easier to boost with another PI at the same time, without requiring ritonavir refrigeration, and this may be particularly useful in this setting.