Background: Prodromes are repetitive complexes of signs or symptoms portending attacks of certain chronic diseases. Recent data suggest that a large majority of patients with Hereditary Angioedema (HAE) have experienced prodromes and able to predict the onset of oncoming attacks. However, prodromes and their clinical significance have not been investigated in a systematic manner and the underlying pathophysiologic basis is unknown. A disease-specific, patient-reported outcome (PRO) instrument suitable for evaluation of prodromes and attacks is an unmet clinical need. We sought to examine and evaluate prodromes and attacks of HAE and its associations, by a new validated PRO instrument (HAE-EPA). Methods: HAE patients participated in a preliminary survey addressing their demographics, social and medical status. A cohort of 66 patients was asked to report their recent experience in prodromes and attacks. Domains (i.e. body locations) and dimentions (i.e. severity, impairment, functionality) were pre-defined for both episodes. Robust bio-statistical methods were used to analyze associations and correlations between both events. Results: Significant correlations were demonstrated between the two interrelated phenomena. Corrleations in severity were high across all domains. Hierarchical Regression analysis demonstrated an interaction between prodromes and the patients’ experience in illness (i.e disease duration). The later can explain associations between patient perception of the intensity of the prodromes and attacks. Conclusions: By using the new instrument HAE patients could effectively distinguish prodromes from attacks. The new validated instrument demonstrated high discriminative ability, acceptability, content validity/reliability, and therefore can be used for the investigation and reporting prodromes, attacks and their relationships.