OBJECTIVES: Hereditary angioedema (HAE) is a rare and potentially life-threatening condition. The efficacy of acute HAE treatments has not been assessed in head-to-head comparative studies. This study aimed to establish the relative efficacy of icatibant [Shire HGT] versus C1-esterase inhibitor concentrate (C1-INH) [CSL Behring], C1-INH [ViroPharma], rh-C1-INH [Pharming], and ecallantide [Dyax]. METHODS: A systematic literature review identified nine relevant randomised clinical trials. Indirect comparison (IC) hazard ratios (HR) between treatments were calculated using the methods of Bucher et al (1997) and Song et al (2003). To account for trial heterogeneity, five sets of icatibant data were considered separately; three clinical endpoint definitions (time to onset of primary symptom relief, time to initial symptom improvement [subject-assessed], and time to onset of symptom relief based on composite VAS score); and three rescue medication (RM) censoring methods (no censoring [RMs ignored], censoring subjects who took RMs prior to onset of symptom relief, and resetting time to onset of symptom relief to 24 h for censored subjects) were considered separately in the ICs. RESULTS: The IC considered each of the 45 icatibant data/endpoint definition/RM censoring combinations. HR estimates favoured (HR ≥1) 37/45 icatibant combinations versus C1-INH [CSL Behring] 20 IU/kg (Median HR = 1.39 [minimum 0.72, maximum 2.10]), 45/45 (29 statistically significant) versus C1-INH [CSL Behring] 10 IU/kg (Median HR = 2.19 [minimum 1.07, maximum 3.39]), 32/45 versus C1-INH [ViroPharma] (Median HR = 1.36 [minimum 0.63, maximum 2.22]), 24/45 versus rh-C1-INH 50 IU/kg (Median HR = 1.04 [minimum 0.48, maximum 1.70]), and 43/45 versus ecallantide (Median HR = 1.67 [minimum 0.75, maximum 2.66]). CONCLUSIONS: Icatibant showed improved time to symptom relief when compared with C1-INH [CSL Behring] 10 IU/kg. No clear differences were evident versus either C1-INH [CSL Behring] 20 IU/kg (SmPC dosing) or the three other HAE treatments.