Due to the low prevalence of afibrinogenemia, epidemiologic data on afibrinogenemia are limited, and no data are available on health-related quality of life (HRQoL). We conducted a cross-sectional international study to characterize the clinical features, the fibrinogen supplementation modalities, and their impact on HRQoL in patients with afibrinogenemia. A total of 204 patients (119 adults and 85 children) from 25 countries were included. The bleeding phenotype was severe: 68 (33.3%) patients having at least one bleed per month and 48 (23%) a history of cerebral bleeding. About 35% (n = 72) of patients were treated with fibrinogen concentrates or cryoprecipitates as prophylaxis, 18.1% (n = 37) received ≥1 injection per week, and 16.6% (n = 34) were on home treatment. A thrombotic event was reported in venous and/or arterial territories by 37 (18.1%) patients. Thrombosis occurred even in young patients, and recurrence was frequent (7.4%). The total HRQoL was lower in children than in adults. Discomfort linked to treatment and limitations to sports and leisure were the main concerns. Women and children were particularly affected in family relationships. In multivariate analyses, younger age, residence in Asia or Africa, and a previous thrombotic event were statistically correlated with a worse HRQoL. In summary, our study underlines the severe bleeding and thrombotic phenotype and their impact on HRQoL in afibrinogenemia. The optimal strategy for fibrinogen supplementation needs to be determined. This trial was registered at www.clinicaltrials.gov as #NCT03484065.