BackgroundHereditary angioedema (HAE) attacks are unpredictable, cause a substantial and enduring burden of illness, and are potentially fatal. Due to issues unique to the US healthcare system, there is a need for a US-validated HAE-specific Quality of Life (QoL) instrument. ObjectiveTo develop and validate a US HAE-specific QoL instrument, following FDA guidelines and established methodologies. MethodsWe generated 41 QoL-related items likely relevant to US HAE-C1INH patients and performed a 10-patient pilot study to refine the question-wording. 415 HAE C1-inhibitor (C1INH) deficiency U.S. patients completed the initial 41-item instrument online, providing the data for item reduction, factor analysis, and the assessment of validity and reliability. We used multiple linear regression to identify the drivers of total and domain scores. Convergent validity analysis assessed the extent to which the HAE-C1INH-QoL is theoretically related to the angioedema-QoL (AE-QoL). ResultsItem reduction and factor analysis yielded a final instrument of 31 items across five domains, and the assessment analysis showed that the HAE-C1INH-QoL is valid and reliable. Attack frequency and severity were statistically significant factors influencing total and domain scores. Correlation analysis of the two instruments indicated that 8 items of the HAE-C1INH-QoL were not included or well-described in the AE-QoL. ConclusionThe HAE-C1INH-QoL is the first HAE-specific QoL tool validated in the US. Compared to the AE-QoL, the items in our instrument are more relevant to US HAE patients.