OBJECTIVE The aim of this study was to compare the cost per unit of effectiveness (successful treatment episode) of 2 highly active antiretroviral therapy combinations-emtricitabine/tenofovir DF + efavirenz (TVD + EFV) and lamivudine/zidovudine + efavirenz (COMB + EFV)-in antiretroviral-naive, HIV-1-infected patients from the perspective of costs to society. METHODS This cost-effectiveness analysis was modeled using a decision tree that considered the therapeutic response (successful treatment episode, ie, HIV-1 RNA <400 copies/mL using data obtained directly from a clinical trial) and the switch to rescue therapy in nonresponders. The time horizon was 24 months of treatment. Cost was defined as direct medical costs (drugs, diagnostic and/or laboratory tests, treatment of adverse effects) and indirect medical costs (productivity losses). All data are presented as euro(2005). Sensitivity analysis was 1-factor threshold, adjustment of ex-factory cost, only direct costs, and applying discount rate in the study. The results are presented as incremental costs, success rates, and cost per patient with undetectable viral load or additional success. RESULTS The expected 48-week cost of the regimen that includes TVD + EFV was euro46,464, and for the regimen that included COMB + EFV, euro56,198. Therefore, savings of euro9734 were achieved for each patient treated with TVD + EFV, as well as a gain of 13% of patients with undetectable viral load after 24 months of treatment. Consequently, treatment with TVD + EFV combination would be dominant in therapy for antiretroviral-naive, HIV-1-infected patients. Sensitivity tests supported the stability of the base-case analysis. The cost-effectiveness ratios were euro619.52 for the TVD + EFV regimen versus euro906.41 for the COMB + EFV regimen. CONCLUSIONS Based on the results of this analysis, patients who started treatment of HIV-1 infection with combination TVD + EFV had significantly lower health care resource utilization and overall treatment costs compared with the COMB + EFV combination.