Self-reported measures of health-related quality of life (HRQOL) are increasingly used in clinical management and evaluation of patient outcomes. HRQOL measures are used to monitor patient progress and treatment response, investigate effects of medical interventions, and provide patient-based data for quality improvement initiatives and policy decisions. Given the importance of HRQOL, it is imperative that the instruments used to assess HRQOL are precise, valid, reliable, and responsive, and that the HRQOL data are appropriately collected, analyzed, and presented. This article reviews the key attributes of studies involving HRQOL data, discusses best practices for selecting appropriate instruments, and provides guidelines for the assessment, analysis, and presentation of these data. A checklist and a reviewer guide are included to serve as templates for authors and reviewers when submitting and reviewing studies involving HRQOL. CHEST 2020; 158(1S):S49-S56 KEY WORDS: CHEST reviews; health-related quality of life; research-clinical; review General Overview of Study Design Measures of health-related quality of life (HRQOL), a type of patient-reported outcome (PRO), are increasingly included as outcomes in clinical trials and comparative research studies. They are used to inform patient-centered clinical decision-making and health policy. 1,2 Measures of HRQOL are patients' perspectives of their health and include symptoms, functional status, and satisfaction ratings. An understanding of the effect of medical therapies on HRQOL can help to inform clinical decisions. 3 Measures of HRQOL have detected differences in outcomes of interventions not identified with traditional clinician-reported measures. 4,5 Measuring HRQOL enables providers to understand conditions and treatment effects from the patient's perspective, enhancing their communication with the patient and facilitating shared decision-making. Given the importance of PROs and HRQOL, the American Heart Association and the US Food and Drug Administration both recommend the increased use of these instruments in clinical care and research trials. 3,6 To make appropriate conclusions regarding HRQOL data, instruments must be based on a conceptual framework and show valid and reliable measurement properties. The interpretation of HRQOL data includes psychometric and statistical methods that may be less familiar to researchers and reviewers than techniques used in clinical