Rilpivirine (RPV) is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) of the diarylpyrimidine family. RPV can be given once daily, is well absorbed and should be administered with food. It is eliminated mainly by hepatic metabolism. Two phase III noninferiority trials (ECHO and THRIVE), compared RPV 25mg with efavirenz (EFV) 600 mg, both given once daily, and combined with 2NRTI backbone. At week 48, response rate for pooled data were 84 versus 82% (difference: 2%; 95% CI: -2.0 to 6.0%). EFV arms performed better than RPV arms when at higher baseline HIV RNA, so RPV was approved for treatment-naïve patients with HIV RNA below 100,000 copies/ml. Approximately 90% of viruses phenotypically resistant to RPV showed cross-resistance to ETR. Conversely, phenotypic analysis showed that in EFV arm, none were resistant to the second-generation NNRTIs. CD4 count increases were similar between groups, but RPV showed a lower rate of discontinuation due to adverse events and lower rates of central nervous system effects, rash and lipid abnormalities. Potency, tolerability and co-formulation in a single tablet (Eviplera(®), Complera(®)) make this drug a new and attractive option for the treatment of HIV.