Health-related quality of life (HRQoL) is increasingly implicated in contemporary hemophilia management. This study focuses on the assessment of HRQoL in Greek patients with hemophilia and the comparison with normative data from the general population, as well as on the extent arthropathy may affect the patients' HRQoL. One hundred and nine adult patients completed the Greek social functioning (SF-36) and Haem-A-QoL questionnaires. Arthropathy was assessed by both the World Federation of Hemophilia clinical score and Pettersson radiological score. The most impaired domains of Haem-A-QoL were sports/leisure (SL) and physical health (PH; mean scores 61.2 and 42.2, respectively). The patients experienced statistically significant lower mean scores in all SF-36 domains than the normative sample, especially in role physical (RPH), bodily pain (BP), and general health (GH) subscales. Among Haem-A-QoL subscales, SL and PH were found strongly associated with severity of arthropathy using both orthopedic scores ( P < .001), and maintained the statistical significance after adjustment for age ( P < .05). A poor orthopedic status was also negatively associated with certain SF-36 subscales. However, none of these correlations remained after adjustment with age. Compared to normative data from Greece, patients with hemophilia showed deterioration in all HRQoL subscales, with a more pronounced effect in RPH, BP, and GH subscales. Health-related quality of life was strongly influenced by arthropathy, mainly in the physical aspects of HRQoL. The use of the disease-specific Haem-A-QoL tool can capture additional associations between HRQoL and hemophilic arthropathy.