The objective of this study was to evaluate the association between self-reported functional status and quality of life in adults with and without chronic conditions. Data were obtained on functional status (Sickness Impact Profile, SIP), and perceived quality of life (Perceived Quality of Life Scale, PQoL) from 454 persons in nine groups with widely varying levels of functional status and disability. Multiple regression was used to analyze the association controlling for demographic characteristics (age, gender, educational level, income, marital status), self-rated health status, and depressive symptoms. PQoL was lowest for persons using wheelchairs and highest for older well adults. Scores decreased as SIP scores increased. Overall, being older, reporting better functional status, and having fewer depressive symptoms were significantly associated with higher quality of life (adjusted R(2) = 0.60). This pattern held for most subgroups, although the association was much lower for adults with AIDS and younger well adults where ceiling effects were observed in functional status. Functional status and perceived quality of life are highly associated but are distinct in many populations. Depressive symptoms and self-rated health are important mediators of the relationship to include in future studies. Amelioration of depressive symptoms through environmental modification and individual treatment are potential strategies for improving on this association in adults with chronic conditions.