OBJECTIVES: Evaluate the cost associated with the ADRs from the use of boceprevir (BOC) or telaprevir (TLP) in patients treated with protease inhibitors (PI) in the SES. METHODS: A multicenter observational study of cohort ITT, extracting the necessary data from the information systems of SES, from September 2012 to December 2013, for patients treated with TLP or BOC was performed. Those co-infected patients (HIV or HBV), in liver transplant or with history of hepatocellular carcinoma were excluded. ADRs assessed were alopecia, fever, retinitis, itching, weight loss, rash, thrombosis, neutropenia, hemorrhoids, stomach pain, amenorrhoea, arthralgia, anxiety and the number of infiltrated blood received by patients. To assess the pharmaceutical cost of ADRs the retail price + VAT at Official List were taken, and to other public health costs SSPE prices, the NHS and records of unit costs were taken also. RESULTS: Withdrawals caused by ADRs were higher for TLP (12.2% vs 8.1%, p = 0.09), frequency of pruriginous erythema (44.9% vs 4%, p <0.001) and anemia (69.4 % vs. 52%, p = 0.142). For BOC, there were higher percentages of dysgeusia (16% vs. 0%, p = 0.011), and neutropenia (52% vs. 24.5%, p = 0.018). The results showed a significant difference between the treatment cost per patient associated with ADRs caused by BOC (€ 5,896) compared to the TLP (€ 11,234), for 34.7 weeks (BOC) and 25.9 weeks (TLP).  CONCLUSIONS: In view of the results obtained, it shows that means a lower costs for the health system ―in the treatment of ADRs due to the use of PI in patients with hepatitis C― patients receiving BOC versus TLP. Postmarketing observational studies are needed to determine the actual efficacy and safety of new drugs.