Darunavir is a new-generation nonpeptidic HIV protease inhibitor (PI), used with low doses of ritonavir for pharmacologic enhancement (boosting). It has demonstrated potent activity against multidrug-resistant HIV, with a robust resistance profile and a distinct set of mutations. In heavily treatment-experienced patients with HIV infection, darunavir administered twice daily with ritonavir has shown higher rates of efficacy than the control PI. In less treatment-experienced patients, boosted darunavir was noninferior to boosted lopinavir. In treatment-naive patients, boosted darunavir administered once daily was noninferior to boosted lopinavir, and showed higher virologic and immunological response rates in patients with high baseline viral load and low baseline CD4(+) cell counts. Monotherapy with boosted darunavir is an acceptable option in some specific conditions. Boosted darunavir was generally well tolerated, with lower incidence of diarrhea and a more favorable lipid profile than boosted lopinavir in treatment-naive patients.