BACKGROUND: The United States has a culturally and demographically diverse populace, and the aim of this study was to examine differences in health preferences by sex, age, ethnicity, and race. METHODS: We assessed preferences for health outcomes defined by the PROMIS-29 survey in a sample of the US population. On the basis of the survey's 540 paired-comparisons trading off lifespan and 7 domains of health-related quality of life (HRQoL), we compared the choices between men and women, adults age 18-54 years and 55 years and older, Hispanics and non-Hispanics, and non-Hispanic blacks and whites. For each subgroup, we estimated the value of 122 HRQoL outcomes on a quality-adjusted life year scale and tested for subgroup differences. RESULTS: Compared with men, women preferred reduced lifespan over losses in HRQoL, particularly for depression. Compared with the younger adults, older adults preferred reduced lifespan over the symptoms of depression, anxiety, and fatigue. Compared with non-Hispanic whites, Hispanics preferred reduced lifespan over depression and sleep disturbance, but held similar values on losses in physical functioning. Among non-Hispanics, blacks preferred reduced lifespan over losses in ability to climb stairs and to fall asleep compared with whites, but held similar values on mental health outcomes. CONCLUSIONS: With the growing emphasis on patient-centeredness and culturally sensitive treatment, it is important to recognize the diversity in values placed on potential losses in HRQoL, particularly mental health outcomes. Demographic differences in preferences may influence comparative or cost effectiveness of treatments as perceived by one or another subgroup.