The Angioedema Quality of Life Questionnaire (AE-QoL) is an angioedema (AE)-specific validated questionnaire, which surveys the quality of life of diagnosed patients. The questionnaire has been used in multiple clinical trials. Our aim was to investigate how the questionnaire can assist physicians in the everyday practice of following up and managing C1-inhibitor deficiency patients. In a prospective trial conducted in our center between 2016 and 2018, 125 hereditary angioedema and 10 diagnosed with acquired angioedema completed an AE-QoL during their annual follow-up visit. Laboratory indices (i.e., complement levels) were obtained for each patient. Statistical analysis comparing clinical data with QoL parameters was performed. Results of the analysis show that AE-QoL total score and number of AE attacks per year correlated well (r = 0.47; p < 0.0001). Women reached higher AE-QoL total score values than men, over a 3-year period (p = 0.0014). The highest AE-QoL total scores were reached by the 41–60-year age group; we obtained a similar result, when analyzing the four domains. No correlation was found between the AE-QoL total score and complement parameters. Patients with a negative correlation between AE-QoL total score and number of AE attacks had a positive correlation with psychologic attributes like fatigue/mood and fears/shame domains. Patients that acquired HAE showed a significant correlation between the annual number of AE attacks and the AE-QoL total scores (r = 0.46; p < 0.0001). The study establishes the use of AE-QoL as a clinical tool for follow-up which can help in the complex assessment of both hereditary and acquired HAE patients, and help to develop better therapeutic strategies.