OBJECTIVES: Favorable clinical outcomes in HIV-1 infection require optimal adherence to multi-drug antiretroviral (ARV) regimens.  Single-tablet regimens (STRs) simplify treatment compared with multiple-tablet regimens (MTRs) and are associated with improved adherence, improved virologic outcomes and reduced hospitalizations.  To date, models assessing the economic value of STRs have been based only on clinical trial evidence from idealized settings with close follow-up. Economic models have not yet incorporated real-world evidence comparing adherence and effectiveness between STRs and MTRs.   METHODS: A patient-level simulation model was used to compare health and economic outcomes between STRs and MTRs in the US.  STRs included EVG/COBI/FTC/TDF, EFV/FTC/TDF and RPV/FTC/TDF. MTRs included a 3^rd agent plus 3TC+TDF backbone.  Before incorporating real-world evidence, the model was validated against published economic projections based on clinical trial results.  Real-world evidence identified via systematic literature review was then incorporated for differences in adherence, resistance, and hospitalization risk between STRs and MTRs. Upcoming generic drug scenarios included 25-75% cost reductions and lower average drug costs for MTRs vs. STRs by $1,300 to $6,100 per year.  All costs were inflated to 2013 USD.   RESULTS: After incorporating real-world evidence, the virologic suppression rates at 24 weeks were 72.7% and 63.2% for STRs and MTRs, respectively. When initiating with STRs vs. MTRs, short-term inpatient costs (at 2 years) were reduced by 29% ($7,660 vs. $10,819) and an additional 2 life years (20.6 vs. 18.6) were gained.  The discounted life-time incremental cost-effectiveness ratios ranged from ~$26,000 to $52,000 per QALY, depending on assumed generic discounts.   CONCLUSIONS: STRs have demonstrated superior clinical and economic outcomes compared to MTRs in real-world settings.  Incorporating this evidence into a cost-effectiveness model illustrated that initiation with STRs is a cost-effective strategy compared with initiation with MTRs, due to greater real-world adherence and effectiveness, and reduced inpatient costs.