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OBJECTIVE:: A 96-week clinical study was planned to estimate the antiviral activity and safety of lersivirine in treatment-naïve HIV-1-infected patients. METHODS:: This ongoing international, multicenter, double-blind, randomized, Phase IIb exploratory study evaluates the efficacy and safety of two doses of lersivirine or one of efavirenz, each combined with tenofovir disoproxil fumarate (DF)/emtricitabine. Patients were randomized 1:1:1 to receive lersivirine (500 or 750 mg once-daily [QD]) or efavirenz (600 mg QD), each administered with tenofovir DF/emtricitabine (300 mg/200 mg QD). The primary endpoint is the proportion of patients with HIV-1 RNA <50 copies/mL (missing/discontinuation=failure) at Week 48. RESULTS:: For the 193 patients in the study, baseline mean plasma HIV-1 RNA was 4.7 log10 copies/mL, and median CD4 cell count was 312 cells/mm. At Week 48, the percentage of patients with HIV-1 RNA <50 copies/mL was 78.5% (51/65), 78.5% (51/65), and 85.7% (54/63) in the lersivirine 500 mg, 750 mg and efavirenz groups, respectively. CD4 cell count changes from baseline were similar across groups. Virologic failure occurred in seven patients (11%) in each of the lersivirine groups and three patients (5%) in the efavirenz group. The pattern of lersivirine resistance was distinct from other non-nucleoside reverse transcriptase inhibitors. Overall incidences of all-causality, treatment-related or Grade 3/4 adverse events (AEs) or AE-related discontinuations were lower with lersivirine than with efavirenz, and serious AEs occurred at similar rates across treatment groups. CONCLUSIONS:: Both lersivirine doses showed broadly comparable efficacy to efavirenz over 48 weeks in treatment-naïve patients, with different AE profiles from efavirenz.