Health-related quality of life (HRQoL) and well-being are concepts that attempt to objectively capture a person's subjective perceptions of vitality and energy. Our objectives were to determine HRQoL and well-being in adult patients diagnosed with inflammatory myopathy who attended at our outpatient clinic and to investigate clinical and biological correlations with these concepts. Sixty-two patients (52 women), with a mean age of 50.7 years, were evaluated in this cross-sectional study-47 with dermatomyositis and 15 with polymyositis. Disease damage and activity were assessed with the International Myositis Assessment and Clinical Studies-validated instruments. Manual muscle testing was used to evaluate muscle strength. Quality of life was evaluated with the WHO instrument (WHO Quality of Life Measure (WHOQOL-BREF)), adapted for use in the Spanish population, and well-being with the WHO-Five Well-Being Index (WHO-5). t tests were conducted to examine differences in HRQoL and well-being outcomes in relation to several disease- and patient-related variables. Correlation analyses were performed with the Pearson correlation coefficient. None of the clinical or biological variables analyzed was significantly associated with a poorer HRQoL or well-being. No differences in HRQoL or WHO-5 well-being score were found between the two myositis subgroups (dermatomyositis vs. polymyositis). Disease activity and muscle weakness were negatively associated with the physical and environmental domains of the HRQoL, respectively (p < 0.002), but not with well-being. Disease duration did not have a significant impact on HRQoL or well-being. In adult patients with myositis, disease activity and muscle weakness are associated with poorer HRQoL in the physical health and environmental domains, respectively.