OBJECTIVES: Rare diseases (RD) are an important bench test case for healthcare services organization. This for both moral and ethical aspects which implies knowing how to cope with the needs of a vulnerable sector of population. At the same time RD its a challenge for healthcare service organizations,  which are called to respond to  particularly emphatic individual requirements. METHODS: The study has been developed on administrative database of the Regional health care system of Lombardia Region, containing all the services provided to resident population and the related costs (or tariffs recognized by the the Regional System). The analysis includes all the citizen benefiting of an exemption from copayments due to a  rare diseases condition. The RHS (regional health care system) perspective has been adopted. RESULTS:  The analysis covered 44,548 subjects with copayment exemption due to RD. The prevalence (2012) was equal to 0.46% of the resident population, with a significant gender difference: 0.39% for males and 0.53 % for females. The average annual expenditure per rare diseased patient amounts to € 5,003.1, a value approximately comparable to the average one for patients with at least two chronic conditions (€ 4,500.2). In terms of gender the figure for women (€ 3,539.3) is significantly lower than that for males (€ 6,856.6). The total impact on RHS is € 222.9 M, equal to 1.21% of regional spending. Patients with ultra rare disease are characterized by costs (€ 6,953.6 pro capita) significantly above the average. CONCLUSIONS: the research give some original insight on the prevalence and economic impact of RD patients in a large population. It permits to appreciate the potential organizational and economic impact od RD patients, especially of those with an ultra-rare condition, as well as financial risk for the local health care units due to prevalence concentration.