GS-US-216-0114 is a phase III, non-inferiority, double-blind randomized trial of 192 weeks duration. Naïve HIV-1 infected adults received either cobicistat once daily (n = 344) or ritonavir 100 mg once daily (n = 348), both in combination with atazanavir and tenofovir/emtricitabine once daily. By intention to treat using the snapshot algorithm, the proportion of patients with HIV-1 RNA < 50 copies/ml at week 48 was 85.2% in the cobicistat group, compared with 87.4% in the ritonavir group (difference -2.2%, 95% CI -7.4% to 3.0%), showing noninferiority of cobicistat versus ritonavir as pharmacoenhancer of atazanavir. Discontinuation for adverse events was similar in both groups, 7% vs 7% in the cobicistat and ritonavir groups respectively, while percentages of patients with serious adverse events were 10% and 7%, respectively. Median increases in serum creatinine level were 0.13 and 0.09 mg/dL, respectively. Non significant lower elevations in fasting lipids were seen in the cobicistat group. Twelve patients in each group met criteria for resistance testing (not achieving HIV-1 RNA < 400 copies/ml or confirmed HIV-1 RNA rebound ≥ 400 copies/ml at or after week 8. No patients developed resistance to protease inhibitor or tenofovir. Emergence resistance to emtricitabine developed in 2 patients on cobicistat and none on ritonavir.