Hereditary angioedema due to C1 inhibitor (SERPING1) deficiency (C1-INH-HAE) is characterized by unpredictable and variable attacks of cutaneous andmucosal edema carrying amajor impact on daily life. While stress and psychological factors are usually suggested as trigger factors of HAE, they have not been sufficiently investigated. Our aim is to study, for the first time in a group of pediatric patients, the role of psychological stress and emotion regulation competence in the variability of attacks ofC1-INH-HAE. The study involved 12 children aged 6–14with a diagnosis of C1-INH-HAE [a diagnosis of C1-INH-HAE must be based on presence of 1 major (1–3) clinical criterion and 1 laboratory criterion] as well as their parents in the following: (1) a qualitative analysis of parent interviews on disease variability and (2) a quantitative evaluation of the psychological profile, perceived stress levels, and emotion regulation competence of the young patients. In the interviews, 91% of parents believe emotional and stress factors are involved in triggering C1-INH-HAE. Fifty-five percent of the young patients report a limitation in their daily activities [Child Behavior Checklist (CBCL)], 83% of them experience an above-average number of stressful events [Coddington Life Events Scale (CLES)], and 91% of them manifest deficits in recognizing and naming emotions [Alexithymia Questionnaire for Children (AQC); Level of Emotional Awareness Scale for Children (LEAS-C)]. Our data show that parents believe psychological stress to be involved in the onset of HAE attacks and children show high levels of stress and broad deficits in the emotion regulation competence. Whether stress is a trigger or a secondary effect of the disease experience, we suggest that improving patients’ emotion regulation competence may increase their resilience to stress, ultimately leading to a better management of the illness