Under the U.S. Lung Allocation Score (LAS) system, older and sicker patients are prioritized for lung transplantation (LT). The impact of these changes on health-related quality of life (HRQL) after transplant has not been determined. In a single-center prospective cohort study from 2010 to 2016, we assessed HRQL before and repeatedly after LT for up to 3 years using the SF12-Physical and Mental Health, the respiratory-specific Airway Questionnaire 20-Revised, and the Euroqol 5D/Visual Analog Scale utility measures by multivariate linear mixed models jointly modeled with death. We also tested changes in LT-Valued Life Activities disability, BMI, allograft function, and 6-min walk test exercise capacity as predictors of HRQL change. Among 211 initial participants (92% of those eligible), LT improved HRQL by all 5 measures (p < 0.05) and all but SF12-Mental Health improved by threefold or greater than the minimally clinically important difference. Compared to younger participants, those aged 65 improved less in SF12-Physical and Mental Health (p < 0.01). Improvements in disability accounted for much of the HRQL improvement. In the LAS era, LT affords meaningful and durable HRQL improvements, mediated by amelioration of disability. Identifying factors limiting HRQL improvement in selected subgroups, especially those aged 65, are needed to maximize the net benefits of LT. In a prospective longitudinal adult cohort, the authors find that lung transplantation substantially improves health-related quality of life and that this improvement is largely mediated by amelioration of physical disability, though older adults and those undergoing transplantation for diagnoses other than cystic fibrosis derive a smaller benefit in health-related quality of life.