Clinical trial data and real-world experience have shown the nonnucleoside reverse transcriptase inhibitors (NNRTIs) to be an important class of agents for the treatment of HIV. Given their long plasma half-lives, in vitro and in vivo potency against HIV, low pill burdens, and ability to be safely combined with other commonly used medications, the NNRTIs nevirapine and efavirenz are widely used in combination antiretroviral therapies. Observational, retrospective cohort studies among antiretroviral treatment (ART)-naive patients have suggested that efavirenz may be superior to nevirapine in terms of efficacy. Recently, data from the 2NN study, a large, multicenter, multinational, prospective, randomized, head-to-head trial comparing efavirenz and nevirapine, have been reported. The results from this study indicate that ART-naive patients achieved good antiviral response after 48 weeks of treatment with nucleoside reverse transcriptase inhibitors (NRTIs) combined with either efavirenz or nevirapine (viral load >50 copies/mL: efavirenz, 70%; nevirapine bid, 65.4%; nevirapine qd, 70%). Even though central nervous system disturbances occurred more frequently among efavirenz-treated patients and nonclinically significant transaminitis occurred more frequently among nevirapine-treated patients, these adverse events were not statistically significant or mutually exclusive. Given the results of the 2NN study, the selection of one agent or the other for use in clinical practice will depend more upon patient-specific factors than expected differences in antiviral responses.