The levels of the health-related quality of life (HR-QoL) were analyzed in hereditary hemorrhagic telangiectasia (HHT) patients. The Short Form-36 Health Survey (SF-36) was administered to 50 HHT patients and scores were compared to a cohort of 2301 normal subjects. Clinical variables were patient age, illness duration, number of epistaxis episodes in the previous year and hemoglobin levels. Physical functioning, physical role limitations, bodily pain, social functioning, emotional role limitations and the physical component scores were lower among females. In multivariable analyses increasing age was related to lower physical functioning (p < 0.04), physical role limitations (p < 0.008), bodily pain (p < 0.05) and emotional role limitations (p < 0.01), while higher hemoglobin levels improved physical functioning (p < 0.03). The number of epistaxis episodes was negatively associated with physical role limitations (p < 0.009), vitality (p < 0.002), social functioning (p < 0.001), physical component summary (p < 0.001) and bodily pain (p < 0.01). Illness duration was negatively related to the mental component summary (p < 0.004). HHT patients had a lower HR-QoL with respect to normal controls in all domains except for bodily pain. Females had lower scores for several domains. Epistaxis was the most important clinical variable.