BACKGROUND: The possibility of incorporating generics into combination antiretroviral therapy and breaking apart once-daily single-tablet regimens (STRs), may result in less efficacious medications and/or more complex regimens with the expectation of marked monetary savings. A modeling approach that assesses the merits of such policies in terms of lifelong costs and health outcomes using adherence and effectiveness data from real-world U.S. settings. METHODS: A comprehensive computer-based microsimulation model was developed to assess the lifetime health (life expectancy and quality adjusted life-years--QALYs) and economic outcomes in HIV-1 infected patients initiating STRs compared with multiple-table regimens including generic medications where possible (gMTRs). The STRs considered included tenofovir disoproxil fumarate/emtricitabine and efavirenz or rilpivirine or elvitegravir/cobicistat. gMTRs substitutions included each counterpart to STRs, including generic lamivudine for emtricitabine and generic versus branded efavirenz. RESULTS: Life expectancy is estimated to be 1.301 years higher (discounted 0.619 QALY gain) in HIV-1 patients initiating a single-tablet regimen in comparison to a generic-based multiple-table regimen. STRs were associated with an average increment of $26,547.43 per patient in medication and $1,824.09 in other medical costs due to longer survival which were partially offset by higher inpatients costs ($12,035.61) with gMTRs treatment. Overall, STRs presented incremental lifetime costs of $16,335.91 compared with gMTRs, resulting in an incremental cost-effectiveness ratio of $26,383.82 per QALY gained. CONCLUSIONS: STRs continue to represent good value for money under contemporary cost-effectiveness thresholds despite substantial price reductions of generic medications in the U. S.