OBJECTIVES: Aims of this study were to quantify the expenditure for antiretroviral (ARV) treatment in Italy, and to estimate the potential impact of the introduction of generic antiretrovirals in the Italian pharmaceutical market. METHODS: Using a data-set of pharmaceutical expenditure in Italy, we analysed the total expenses for ARVs at national level. Since in the near future generic zidovudine (AZT), lamivudine (3TC), nevirapine (NVP) and efavirenz (EFV) will be available in Italy, we calculated the potential cost-saving, modeling scenarios with price reduction between 20%-60% of the originators prices. In sensitivity analyses, we assumed that branded emtricitabine could be substituted by generic 3TC, and that fixed dose combinations (FDC) could be partially substituted by single components with generic medicines. RESULTS: In 2010, €500.689.927 were spent for antiretroviral therapies (total ARV use: 1.91 DDIs/1000 inhabitants/day), with an increase of 12.6% compared with the 2009 expenditure. The most relevant proportion was attributable to FDC, accounting for €238.826.599 (47.7% of total costs). The total percentage of costs for ARVs related to the use of AZT, 3TC, NVP and EFV was 7.33% (€36.713.056). Assuming the prescriptions of these drugs to be constant in next years, different scenarios of price reduction (from 20% to 60%) for generic drugs showed an estimated cost-saving ranging from €7.342.611 (1.47% of total ARV costs) to €22.027.833 (4.40%). When including emtricitabine substitution by 3TC, cost-saving rises to €7.435.738-22.307.213 (1.49-4.46%) and to €26.832.726-80.498.178 (5.36-16.08%) considering the unbundling of branded FDC. CONCLUSIONS: The forthcoming availability of some antiretroviral generics could be an option for safely and effectively cost-saving. However, in our study, the greater reduction of costs has been estimated by FDC substitution, raising the potential dilemma of increasing regimen complexity. Further studies will be needed to evaluate safety and efficacy of FDC substitution with generics incorporating both treatment adherence and pharmacoeconomic outcomes.