OBJECTIVES: This study will evaluate lifetime cost-utility of a therapy based on lopinavir/ritonavir vs atazanavir + ritonavir, using a tenofovir-emtricitabine backbone, in an Italian cohort of HIV infected anti-retroviral-naïve patients. An international literature review revealed, that there are limited useful data to inform Italian decision makers, taking into consideration Country specific costs and utility. METHODS: Starting from the Broder (2011) Markov microsimulation model and CASTLE study data, an Italian model was developed to specify direct costs and health outcomes from Italian HIV-infected patients and their treatment, adopting a national health service (NHS) payer perspective. The Health State (HS) transition probabilities were assessed within a sample of 319 patients on treatment within the Lombardy Region (the probability vector took into consideration the results of the 96-week CASTLE trial, the principal published literature and the evidence related to the Italian population in terms of cholesterol changes, coronary heart disease (CHD) events and adverse events (AEs). Costs related to AEs and to the care of HIV+ patients were correlated to clinical effectiveness data, as well as institutional indications, protocols and reimbursement tariff of hospitals located in Lombardy Region. RESULTS: The newly developed Italian Markov model consisting of 8 HS, informs about the distribution of the Italian population, and forecasting the evolution of the clinical pathway of anti-retroviral-naïve patients through different stages up to death. Clinical effectiveness and absorption of resources were investigated to truly represent the Italian HIV context. CONCLUSIONS: The innovative method of this Markov model construction based on national data, ensures the opportunity of a closer results alignment to specific Italian costs, and to its usability from an Italian decision making and payer’s perspective.