OBJECTIVES: One significant innovation of combination antiretroviral therapy (cART) has been the introduction of a once-daily fixed-dose combination to either maintain or increase treatment adherence. DTG/ABC/3TC is a highly efficacious and well-tolerated once-daily regimen for HIV-infected patients. The objective of the study was to assess the cost-utility (C/U) of treatment initiation with DTG/ABC/3TC single tablet regimen (STR) in ART-naïve HIV infected patients. METHODS: A microsimulation model was developed to compare, from the Spanish Health System perspective, the C/U of treatment inititation with DTG/ABC/3TC vs. the treatment initiation with any of the following regimens: Emtricitabine/Tenofovir/Efavirenz (FTC/TDF/EFV), and Darunavir/r (DRV/r) or Raltegravir (RAL) with Emtricitabine/Tenofovir (FTC/TDF) or Abacavir/Lamivudine (ABC/3TC) over a lifetime horizon. One million subjects were simulated using data from SPRING-2, SINGLE and FLAMINGO trials, each one of them went through a Markov chain to emulate each patient life from initial treatment to death. The health states included were:  living with HIV with or without opportunistic infections, long-term chronic diseases and death. Transition probabilities for each 1-month cycle, were obtained from clinical trials. Utilities and direct health-care costs (€2015) were obtained from literature and national databases. A 3% annual discount was applied to costs and health outcomes. Sensitivity analysis with 0% and 5% discount rates were performed. RESULTS: Treatment initiation with DTG/ABC/3TC was dominant when it was compared with treatment initiation with all the comparators: vs. FTC/TDF/EFV (-67,210.71€/QALY), vs. DRV/r + FTC/TDF or ABC/3TC (-152,411.73€/QALY), and vs. RAL + FTC/TDF or ABC/3TC (-182,480.19€/QALY). All the sensitivity analyses performed showed the consistency of these findings. The main driver of cost was ATR-treatment (about 80%) followed by the costs of care (around 14%).  CONCLUSIONS: With the premises considered, treatment initiation with DTG/ABC/3TC STR appears to be the most cost-effective option in ART-naïve HIV infected patients from the Spanish Health System perspective.