Persons with chronic disease experience multiple symptoms. Understanding the association between these symptoms and health outcomes would facilitate a targeted approach to symptom assessment and treatment. Our objectives were to determine the association of a range of symptoms with quality of life, self-rated health, and functional status among chronically ill adults, and to assess methods for evaluating the independent associations of symptoms that may be interrelated. We consecutively enrolled 226 cognitively intact, community-dwelling adults, aged 60 years or older with chronic obstructive pulmonary disease, heart failure, or cancer. Seven symptoms (physical discomfort, pain, fatigue, problems with appetite, feelings of depression, anxiety, and shortness of breath) assessed using the Edmonton Symptom Assessment Scale were examined for their association with self-rated quality of life, self-rated health, and functional status. Principal component analysis and logistic regression revealed similar results. The latter demonstrated that physical discomfort was associated with lower self-rated health (adjusted odds ratio [OR] 1.9; 95% confidence interval 1.2-2.9) and functional disability (adjusted OR 1.8; 95% confidence interval 1.2-2.7). Feelings of depression were associated with poorer quality of life (adjusted OR 1.7; 95% confidence interval 1.1-2.6), and shortness of breath was associated with lower self-rated health (adjusted OR 1.5; 95% confidence interval 1.1-2.0). The association between a range of symptoms and quality of life, self-rated health, and functional status differed across outcomes, but only three symptoms-physical discomfort, feelings of depression, and shortness of breath-maintained their associations when multiple symptoms were examined concurrently. These findings suggest that interventions targeting these symptoms could improve several health-related outcomes.