OBJECTIVES: In Italy, since 2013, boceprevir and telaprevir, first-generation protease inhibitors, in combination with peginterferon and ribavirin have been approved for HCV (genotype-1) treatment. The aim of this study is to evaluate the real life response rate using sustained viral response (SVR) and associated overall costs in a “difficult-to-treat” cohort. METHODS: Fifty-seven patients, treated at University Hospital “G. Martino” of Messina between June 2013 and March 2014 (30 on telaprevir and 6 on boceprevir, while 6 excluded in the land-in phase), were stratified per: disease severity, previous treatment (naïve or non-responders), adverse drug reactions (ADRs) and co-morbidities. The primary outcome was SVR at 24 weeks after treatment end. Total costs were calculated summing up drugs cost, overall cost of laboratory tests as per clinical guidelines, and the cost to treat ADRs. Ex-factory prices (year 2014, including VAT 10%) were used to estimate drugs costs, while hospital related resource consumption (routine visits and laboratory tests and to treatment of ADRs) was estimated using Regional tariffs. RESULTS: SVR in Real-World cohort was significantly lower than in clinical trials. Overall 39.2% patients were responsive to both treatments, with SVRs being statistically the same in both drugs (p=NS); 96.6% patients in the telaprevir cohort and 71.4% in the boceprevir showed severe ADRs. The most common were anemia, respectively in 70.0% and 42.9% of telaprevir and boceprevir patients, and rash, respectively observed in 63.3% and 14.4% of telaprevir and boceprevir. Management costs were: €31,055 for telaprevir and €26,478 for boceprevir treated patients. ADRs management represented 11.96% and 13.24% of the management cost respectively for telaprevir and boceprevir. CONCLUSIONS: Our study shows that HCV treatment with first-generation protease inhibitors resulted in lower results in real-life and additional costs for ADRs management. Higher cost of second-generation HCV treatments may offset the extra cost by higher SVR and lower ADRs management costs.