Antiretroviral (ARV) treatment strategies for HIV-infected patients continue to evolve. Over the past few years, there was a shift towards the use of nonnucleoside reverse transcriptase inhibitor-based regimens, mostly because of better tolerability, a lower pill burden, and improved adherence relative to using protease inhibitor (PI)-based regimens. Although the 2 strategies do afford similar potency and durability, the PI-based regimens provide a higher genetic barrier to the development of ARV resistance. This has become progressively more important for reasons that include increasing rates of baseline ARV resistance in newly infected patients and the risk of developing ARV resistance in treated populations with suboptimal adherence. With the introduction of novel ARVs and reformulated agents with more convenient dosing requirements, improved tolerability, and unique resistance characteristics, boosted PI-based strategies are increasingly being considered when initiating therapy in ARV-naive patients. In this article, the evidence for the use of boosted PIs as early therapy is reviewed, with emphasis on data available from comparative randomized controlled trials.