OBJECTIVES: In 2012, NICE recommended protease inhibitors as first line treatment for G1 HCV infection. The objective of the analysis was to assess the cost-utility of SMV/PR versus recommended comparator regimens used to treat G1 and G4 patients in the NHS. METHODS: The model involved a treatment phase followed by a post-treatment Markov phase, capturing lifetime outcomes according to whether sustained virologic response (SVR) had been achieved. SMV/PR was compared with PR, telaprevir + PR (TVR/PR), and boceprevir + PR (BOC/PR) in G1 treatment-naïve and treatment-experienced patients. In G4, SMV/PR was compared with PR.  Dosage regimens, including response-guided therapy and futility stopping rules, were based on the EMA approved labels. G1 SVR estimates were derived from a mixed treatment comparison; a matching-adjusted indirect comparison was used for G4. Patient baseline characteristics were drawn from a UK HCV dataset analysis and clinician opinion. Health state transition probabilities, utilities and health state costs were drawn from published UK analyses. Sensitivity analyses were conducted to assess uncertainty around estimated costs and quality-adjusted life years (QALY). RESULTS: The G1 model yielded an ICER for SMV/PR vs PR of £14,206/QALY for treatment-naïve and £9,793/QALY for treatment-experienced patients. SMV/PR dominated TVR/PR and BOC/PR in both patient groups. In G4, the ICER for SMV/PR vs PR was £20,791/QALY and £11,662/QALY for treatment-naïve patients using the two most appropriate studies for matching. The ICER was £12,070/QALY and £8,896/QALY for treatment-experienced patients. In both models, multivariate probabilistic sensitivity analysis revealed that at a willingness to pay of £20,000/QALY, SMV/PR had the highest probability of being the most cost effective intervention, regardless of treatment experience. Results were robust to univariate and scenario sensitivity analyses. CONCLUSIONS: Compared to other regimens currently available within the NHS, SMV/PR is a cost-effective option to treat G1 and G4 HCV patients, regardless of treatment experience.