In 1991, the World Health Organization initiated a project to simultaneously develop a quality of life (QOL) instrument in 15 countries: The World Health Organization Quality of Life (WHOQOL) instrument. This was intended as a generic QOL tool for use with patients across varying disease types, severities of illness, and cultural subgroups. The objective of the current study was to evaluate the WHOQOL-100 in the U.S., one of the original 15 participating countries. The WHOQOL is a 100-item self-report instrument consisting of 24 subscales within six domains: Physical, Psychological, Independence, Social, Environment, and Spiritual. Four additional items pertain to overall QOL/health. We tested the WHOQOL-100 (U.S. version) in a sample of 443 adults (n = 251 chronically ill, n = 128 healthy, and n = 64 childbearing) in the U.S. to test its reliability (internal consistency, test-retest), construct validity (convergent, discriminant), responsiveness, and factor structure. The WHOQOL-100 (U.S. version) has acceptable internal consistency (alpha range: 0.82-0.95 across domains) and reproducibility (ICC range: 0.83-0.96 at 2-week retest interval). It is responsive to change in clinical conditions, as evidenced by predicted score change (effect size) in women after childbirth. Construct validity was demonstrated by (1) its correlation with the Short Form-36 and Subjective Quality of Life Profile, and (2) its ability to discriminate between the diverse samples in this study. The conceptual structure was confirmed exactly with the exception of four facets that did not correlate most highly with the domains to which they were originally assigned, but these differences were minor. The WHOQOL measurement system is suitable for evaluating the QOL of adults in the U.S. The psychometric properties will be continually evaluated as more data become available in the U.S.