At present, the majority of patients who have initiated their first antiretroviral therapy have received a combination comprising a nonnucleoside and two nucleoside analogues. The use of nonnucleosides as first-line therapy has been favored for their more convenient dosing, with less pill numbers, and the possibility of co-formulation with nucleoside analogues. Although protease inhibitors are also considered to be a preferred standard, they have been less frequently used as first regimen of choice because of their adverse effects in the short to medium term. The introduction of darunavir and atazanavir as new protease inhibitors boosted with ritonavir has resulted in a significant change in this area. These drugs show a lower incidence of adverse effects, allow once-a-day administration, and have a high barrier to resistance that prevents the selection of resistance mutations in case of virologic failure. On this basis, it is likely that over the next few years these drugs will become a standard of care, gaining acceptance and being used more frequently as preferred first-line regimen.