OBJECTIVES: To evaluate the cost-effectiveness of icatibant [Shire HGT] 30 mg subcutaneous versus C1-esterase inhibitor concentrate (C1-INH) [CSL-Behring] 20 IU/kg intravenous for moderate to severe attacks of hereditary angioedema (HAE) types I and II in the UK setting. METHODS: A probabilistic cost-utility model was developed over a time horizon of 96 h (the duration of a single acute attack). Comparisons were made for therapy administered at home and in hospital. Quality-adjusted life years (QALYs) were estimated by combining the time to onset of symptom relief with utility weights for the health states before and after onset of symptom relief. Clinical evidence and other model parameters were identified by systematic review. An indirect comparison using previously published methods was conducted. Costs relating to drug acquisition; administration; repeat injections; monitoring and supportive care; hepatitis A and B vaccinations for C1-INH; self-administration training; and adverse events were considered. Probabilistic and univariate sensitivity analyses were conducted. RESULTS: The indirect analysis suggested a non-significant trend towards a reduced time to symptom relief for icatibant when compared with C1-INH. In the economic analysis, there was a non-significant inter-treatment difference in estimated QALYs per attack, equivalent to ~0.75 quality-adjusted life hours in icatibant’s favour. In the base-case analysis (SmPC dosing and NHS list price), total costs per attack were estimated as £1,577 for icatibant and £2,169 for C1-INH; a saving of £592 (95%CI: £394–£715) per attack with icatibant. CONCLUSIONS: This is one of the first comparative health economic models presented for HAE. The systematic approach to data identification and analysis led to successful submissions to SMC and AWMSG in this orphan indication. The analysis demonstrated that icatibant reduces costs versus C1-INH (20 IU/kg at SmPC dosing) when treating acute HAE attacks in the UK setting.