Objectives: Costs may play a role in deciding how and when to start highly active antiretroviral therapy (HAART) in a naive patient. The aim of the present study was to assess the cost-effectiveness of treatment with HAART in a large clinical cohort of naive adults to determine the potential role of single-tablet regimens in the management of patients with human immunodeficiency virus (HIV). An incremental cost-effectiveness ratio analysis was performed, including a quality-adjusted life year approach. Results: In total, 741 patients (females comprising 25.5%) were retrospectively included. The mean age was 39 years, the mean CD4 cell count was 266 cells/mu L, and the mean viral load was 192,821 copies/mL. The most commonly used backbone was tenofovir + emtricitabine (77.6%); zidovudine + lamivudine was used in 10%, lamivudine + abacavir in 3%, and other nucleoside reverse transcriptase inhibitor (NRTI) or NRTI-free regimens in 9.4% of patients. NNRTIs were used in 52.8% of cases, boosted protease inhibitors in 44.1%, and unboosted protease inhibitors and integrase inhibitors in 0.7% and 2.4%, respectively. Starting therapy at CD4>500 cells/mu L and CD4 351-500 cells/mu L rather than at,201 cells/mu L was the more cost-effective approach. The same consideration was not true comparing current indications with the possibility to start HAART at any CD4 value (eg,>500 cells per mu L); in this case, the incremental cost-effectiveness ratio value was (sic) 199,130 per quality-adjusted life year gained, a higher value than the one suggested in guidelines. The single-tablet regimen (STR) invariably dominated any other therapeutic approach. Sensitivity analysis was performed, and starting right away with an STR was cost-effective even when compared with therapeutic strategies contemplating STR as simplification. Conclusion: By integrating clinical data with economic variables, our study offers an estimate of the cost-effectiveness of the various first-line treatment strategies for patients infected with HIV and provides significant evidence to be used in future prospective pharmacoeconomic evaluations.