OBJECTIVES: Through the Italian off-label/compassionate use procedure, regulated by Law 648/96, the Technical Committee of AIFA (CTS) can include a given medication (among innovative drugs authorised abroad, but not in Italy, drugs which have not yet received an authorisation but have undergone clinical trials, and drugs to be used for a therapeutic indication different from the authorized one) in an official list, allowing it to be prescribed at the charge of the National Health System (NHS). This study aimed to assess AIFA’s approach, by reviewing approvals, rejections and methods followed by AIFA for its decisions. METHODS: Reports of CTS meetings from January 2013 to May 2015 were reviewed, checking number and characteristics of drugs under evaluation, and analyzing each single decision taken by CTS. The impact of 648 on pricing and reimbursement decisions was also analysed (both in terms of price and time) RESULTS: Out of 103 applications, 37 (35,9%) received a positive evaluation, 54 (52,4%) a negative evaluation and 12 (11,7%) a conditional approval. The main therapeutic areas represented were oncology/onco-haematology with 29 requests (28,2%), followed by paediatrics with 12 requests (9,2%), non-oncological haematology and cardiovascular, both with 9 requests (6,9% each), neurology and ophthalmology. Several rare disease compounds have been evaluated. Analysis indicated that the drivers for the inclusion in the 648 List were the presence of strong clinical data, the lack of therapeutics alternatives in the Italian market, the rare disease condition and the paediatric indication. CONCLUSIONS: In the last two-and-a-half years, 49 indications have been approved, ensuring new important safe and efficacious therapeutic options. This analysis shows the important role of the Italian Law 648/96, a precious tool for patients to be treated with a drug, with strong clinical and safety data, waiting for the whole Italian regulatory process to be completed.