OBJECTIVES: For first-line treatment of HIV, US treatment guidelines recommend the once-daily tablet of efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF) as a preferred regimen and the once-daily tablet of elvitegravir/cobicistat/emtricitabine/tenofovir (EVG/cobi/FTC/TDF) as an alternative regimen.  This study assessed the clinical and economic trade-offs involved in using EVG/cobi/FTC/TDF compared with EFV/FTC/TDF in first-line HIV antiretroviral therapy (ART) in US adults.  METHODS: A Markov cohort model was developed to project lifetime health-related outcomes, costs, quality-adjusted life years (QALYs), and cost-effectiveness of EVG/cobi/FTC/TDF compared with EFV/FTC/TDF as first-line ART in the US. HIV patients progressed in 12-week cycles through second-line, third-line, and non-suppressive therapies, AIDS, and death. Baseline characteristics and first-line virologic suppression, change in CD4 count, and adverse effects (lipid, central nervous system, rash, and/or renal) were based on 48-week clinical trial results.  These results demonstrated equivalent virologic suppression between the two regimens. Point estimates for virologic suppression (favoring EVG/cobi/FTC/TDF) were used in the base case, and equivalency in scenario analysis. Published sources and expert opinion were used to estimate costs, utilities, AIDS risk, mortality, and subsequent-line CD4 count, efficacy and adverse events. Costs were reported in 2012 US dollars. Sensitivity analyses were conducted to assess robustness of results. RESULTS: Compared with patients initiating EFV/FTC/TDF, patients initiating EVG/cobi/FTC/TDF were estimated to have higher lifetime costs. EVG/cobi/FTC/TDF added 0.087 QALYs over a lifetime at a cost of $10,843, producing an incremental cost-effectiveness ratio of $124,101/QALY gained. Results were most sensitive to first-line response, product costs, and likelihood of renal adverse events. When equivalent efficacy was assumed, EFV/FTC/TDF dominated EVG/cobi/FTC/TDF with lower costs (-$12,305) and greater QALYs (0.047).   CONCLUSIONS: At a societal willingness to pay of $100,000/QALY, EVG/cobi/FTC/TDF was not cost effective in the base case compared with EFV/FTC/TDF for first-line HIV treatment. In scenario analysis assuming equivalent efficacy, EFV/FTC/TDF dominated EVG/cobi/FTC/TDF with lower costs and greater QALYs.