Etravirine is the first next-generation nonnucleoside reverse-transcriptase inhibitor (NNRTI) that is approved for the treatment of HIV infection in patients who have experienced virologic failure while receiving an NNRTI-containing regimen. The drug is taken as two 100-mg tablets twice daily after a meal. Because the drug is metabolized by cytochrome P450 isoenzymes, it cannot be coadministered with a number of other drugs (fosamprenavir, high-dose ritonavir, atazanavir, rifampin, and several antiepileptic medications). Etravirine demonstrates potent in vitro activity against wild-type and NNRTI-resistant strains of HIV. In vitro resistance and treatment failure is associated with the development of multiple NNRTI resistance mutations other than the K103N mutation. Several large clinical studies have documented the benefit of adding etravirine to an optimized background regimen in patients with virologic failure who are infected with multidrug-resistant HIV. The major adverse effects of etravirine therapy are nausea and rash, which are typically self-limiting and do not lead to treatment discontinuation.