ECHO and THRIVE are 2 phase III, non-inferiority, double-blind randomized trial of 96 weeks duration. Analysis of pooled trial data was preplanned. 1368 naïve HIV-1 infected adults received either rilpivirine 25 mg once daily or efavirenz 600 mg once daily, both in combination with a fixed dose of N(t)RTI. In ECHO patients received tenofovir/emtricitabine, and in THRIVE tenofovir/emtricitabine or abacavir/lamivudine or zidovudine/lamivudine, as selected by the investigator. By intention to treat-TLOVR, the proportion of patients with HIV-1 RNA < 50 copies/ml at week 96 was 78% in both groups (difference 0.0%, 95% CI -4.4% to 4.4%), confirming week 48 primary endpoint that rilpivirine was non-inferior to efavirenz. Virologic response was similar in both treatment regimens in various sub-groups.However, virologic response was lower and virologic failure higher for rilpivirine versus efavirenz in patients with 95% or less adherence or baseline viral load > 100 000 copies/ml. Over 96 weeks tolerability was better in the rilpivirine than in the efavirenz group : discontinuation for adverse events (4% versus 9%), treatment-related grade 2–4 adverse events (17% versus 33%), rash (4% versus 15%), dizziness (8% versus 27%), abnormal dreams/nightmares (8% versus 13%), grade 2-4 treatment emergent laboratory abnormalities (46% versus 58%), mainly driven by grade 2–4 lipid abnormalities. Virologic failure was more frequent in the rilpivirine group than in the efavirenz group (14% vs 8%), with emergence of non-nucleoside reverse transcriptase inhibitor resistance-mutations at virologic failure in 53% versus 48%, respectively, and emergence of N(t)-RTI resistance-mutations in 56% versus 26%, respectively.