Background: Chronic histaminergic angioedema (CHA) is defined as recurrent episodes of isolated angioedema (without hives) of unknown cause that respond to the same treatment as chronic spontaneous urticaria (CSU). Quality of life (QoL) studies have not been performed for CHA, except those carried out in the context of CSU associated with angioedema attacks (CSU-AE). Moreover, biomarkers for monitoring disease activity in CHA have not been identified. We aim to describe the burden of CHA and impact on patient QoL, compare the findings to those in CSU-AE patients, and investigate biomarker associations with disease severity and QoL parameters. Methods: We performed a prospective multicenter study that included 68 patients with CHA and 63 patients with CSU-AE. Demographic and clinical variables were collected. Validated patient-reported questionnaires were employed to analyze the quality of life and disease activity. Blood and serological parameters, including blood cell count, C-reactive protein, D-dimer and total IgE, were also analyzed. Results: Angioedema disease activity was significantly higher in CSU-AE patients (median AAS7, IQR: 1, [0–1]) than CHA patients (0, [0–1]; p= 0.022). A considerable impact on QoL was found in both groups, although significantly worse values were found for CSU-AE (median AEQoL, IQR: 37, [10–65]; p=0.005). CHA patients were older than CSU-AE patients, and female predominance was not observed. Conclusions: Angioedema severity and QoL impacts are significantly worse in CSU than in chronic histaminergic angioedema. Angioedema should be included in severity urticaria scores (UAS) as well as in specific quality of life urticaria scales.