OBJECTIVES: Therapies for rare diseases are defined as ‘Orphan Drugs' (ODs). EMEA appoints this status to products at any development stage and scientifically supports companies in the Marketing Authorisation (MA) process. Funding is regulated by country-specific legislation. Scope of this study was to describe the Italian ODs regulation: definition, number of authorized drugs, P&R, time span from designation to European and Italian MA; national funding criteria. METHODS: EMEA-ODs were identified through the official list; authorisation in Italy was retrieved in the Italian Gazzetta Ufficiale. RESULTS: Italian definition of OD reflects European legislation. National rules to identify a cost-effectiveness level for reimbursement are not established. Among 303 ODs by EMEA (1998-2006), 6% are authorised in Italy and 94% are not. 11 out of 18 authorized (61%) (Algasidase-beta, Algasidase-alpha, Arsenic-Trioxide, Laronidase, Bosentan, Imatinib, Mitotane, Miglutat, Pegvisomant, Iloprost, N-carbamyl-L-glutamic-acid) achieved MA through the P&R negotiation process. The remaining 7 (39%) are included in ‘Law-648' list of drugs, for treatment of diseases with ‘no alternative therapeutic path' and fully NHS-reimbursed through a dedicated budget. Generally, Italian MA is obtained 2-4 years after designation and European MA; Bosentan and N-carbamyl-L-glutamic acid obtained MA contextually to European market access; Imatinib obtained MA in Italy first, one year after designation, and 3 years later in Europe. Reimbursement and use are generally limited to hospital setting, except for Arsenic Trioxyde (at full patient's charge) and Bosentan (also in the outpatient setting). Four drugs (rH-interferon-gamma-1b, Mifepristone, Tetrahydrobiopterin, Trientine-dichloride) were designated only few years after the inclusion in the “Law-648” list (1998-2000); Idebenone contextually achieved OD status; Gemtuzumab and Galsulfase within 1-5 years. CONCLUSION: The OD designation by EMEA doesn't necessarily imply Italian MA: 6% of European ODs have currently accessed the Italian clinical practice. As elsewhere in Europe, procedures regulating authorisation and funding criteria aren't fully disclosed yet.