Background Hereditary hemorrhagic telangiectasia is characterized by arteriovenous malformations or telangiectasias in multiple organs. Nose bleeding is the most common manifestation of hereditary hemorrhagic telangiectasia and can be debilitating. Cardiac involvement in the form of high-output cardiac failure is a poorly studied complication of hereditary hemorrhagic telangiectasia. The objective of this study is to describe the natural history of high-output cardiac failure in hereditary hemorrhagic telangiectasia and define the relation between bleeding complications and high-output cardiac failure. Methods In this case-control study at the Washington University hereditary hemorrhagic telangiectasia center, all patients evaluated for hereditary hemorrhagic telangiectasia and found to have high cardiac output between 1999 and 2006 were enrolled as cases (n = 17) and compared with 17 hereditary hemorrhagic telangiectasia controls without high-output cardiac failure. Results During lifetime, cases needed more transfusions, emergency department visits, and hospital admission for nose bleeding. Cases experienced significant worsening of nose bleeding immediately before heart failure diagnosis. During the 2 years before study-related evaluation, 16 (94%) cases needed transfusions every month as compared with 2 (12%) controls ( P <.001). The number of transfusions required during these 2 years also was higher in cases (median 3, range 0-12) as compared with controls (median 0, range 0-1.5, P <.001). Conclusions Hereditary hemorrhagic telangiectasia patients with high-output cardiac failure have significantly greater nose bleeding as compared with patients without high-output cardiac failure. In addition, nose bleeding worsens around the time of development of high-output cardiac failure. Early recognition of the relationship between severe nose bleeding and high-output cardiac failure can lead to earlier diagnosis and provide an opportunity for earlier institution of therapy for high-output cardiac failure.